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Vincent C.O Njar

Vincent C.O Njar Ph.D., (UCL/London)

Academic Title: Professor
Primary Appointment: Pharmacology
Additional Title(s): Head, Medicinal Chemistry Section, Center for Biomolecular Therapeutics (CBT); Institute for Bioscience and Biotechnology Research (IBBR)
Location: 685 West Baltimore Street, HSF 1 Suite: 580-E, Baltimore, MD 21201; 9600 Gudelsky Drive, Suite 314-B, Rockville, MD 20850
Phone: 410-706-6364 (Baltimore); 240-314-6448 (Rockville)
Fax: 410-706-0332 (Baltimore); 240-314-6255 (Rockville)
Lab: 410-706-6365 (Baltimore); 240-314-6451 (Rockville)

Personal History:

Dr. Vincent Njar completed his B. Sc. in Chemistry at University of Ibadan (Nigeria) in 1976 and went on to obtain a Ph.D. in Organic Chemistry in 1980 from University College London (UK) under the supervision of Derek V. Banthorpe. Following two years of postdoctoral research with the late Eliahu Caspi at Worcester Foundation for Experimental Biology, Shrewsbury, Mass. (USA), he joined the Department of Chemistry at the University of Ibadan (Nigeria) as Lecturer II. He was promoted through the ranks and became Professor of Organic Chemistry in 1996.

During his tenure at University of Ibadan, he was visiting Professor at several institutions, including: Johns Hopkins University, Baltimore, USA (1988, 1989, 1992 & 1993); Universite de Sherbrooke, Sherbrooke, Quebec, Canada (1990); University of Southampton, Southampton, UK (1991, 1992 & 1995); and University of Saarland, Saarbruecken, Germany (1994-1995). During these research visits he collaborated with eminent scholars including: Professors Eliahu Caspi (Worcester Foundation), Cecil Robinson (Johns Hopkins), Liat Tan (Sherbrooke), Muhammad Akhtar (Southampton) and Rolf Hartmann (Saarland). Theses research visits were made possible by grant and fellowship awards from US National Institutes of Health, Bethesda, USA; (Fogarty International Research Fellowship) International Union Against Cancer, Geneva, Switzerland; Medical Research Council of Canada; Alexander von Humboldt Foundation, Bonn, Germany (Alexander von Humboldt Fellowship) and Wellcome Trust Foundation, London, UK.

Following several research visits from 1996 to 1998 collaborating with Dr. Angela Brodie at University of Maryland, Baltimore (UMB), he was appointed Assistant Professor of Pharmacology in 1999 and was promoted to Associate Professor in 2002. In 2008, Dr. Njar was appointed Professor of Medicinal Chemistry and Oncopharmacology at Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA, USA. Finally, in January 2012, he came back to UMB as Professor of Medicinal Chemistry and Pharmacology and Head, Medicinal Chemistry Section of the newly established Center for Biomolecular Therapeutics (CBT).

Dr. Njar actively participates in several drug discovery and development grant review committees and he is a Charter Member of NIH/NCI’s Drug Discovery and Molecular Pharmacology (DMP) Grant Review Study Section; NIH/NCI’s Small Business Cancer Drug Development and Therapeutics (CDDT) Study Section and Scientific Reviewer for US Department of Defense (DOD) Prostate and Breast Cancer Research Programs; and AACR-Millennium Fellowship in Prostate Cancer. He is also grant reviewer for several foreign agencies in the United Kingdom, Australia, Singapore and Qatar. His research is currently supported by the US National Institutes of Health (NIH), the National Cancer Institute (NCI) and US Veteran Administration (VA).

Research Interests:

Dr. Vincent C. O. Njar has a long standing interest in the rational discovery and development of small molecules as anti-cancer agents. The major objective of my current research is to design, synthesize, and evaluate novel patentable compounds in suitable model systems with potentials to prevent and/or treat breast and prostate cancers. I am also interested in understanding mechanisms of anti-cancer actions of the novel agents. My research is at the interface of medicinal chemistry and pharmacology/oncology. My research is interdisciplinary and has strong therapeutics translational potentials. My overall research strategy is presented in the schematic below.

Lab Techniques and Equipment:

Organic & Medicinal Chemistry (small molecule synthesis, NMR, IR, HRMS, HPLC, UHPLC,), Molecular Modeling, Use of modern chromatographic and spectroscopic tools for purification, structure identification and stability analyses of small molecules, Oncopharmacology (prostate and breast cancers), Experimental Therapeutics, Molecular Biology, In Vivo novel agents testing (toxicology, preliminary pharmacokinetics, pharmacodynamics, anti-tumor efficacy assessments) techniques are used in Dr. Njar’s Laboratory

Laboratory Personnel:

Current Personnel

Dr. Lalji K. Gediya

I obtained a Ph.D. degree in Pharmaceutical Chemistry from the University Institute of Chemical Technology (UICT), Mumbai, India in 1999. After brief stints at Atul Limited and USV Limited, Mumbia, India, I joined Dr. Vincent Njar’s Lab in 2004 as a Postdoctoral Fellow and was promoted to the ranks of Research Instructor and Research Associate in 2008 and 2012, respectively. My current research concerns the rational design and synthesis of novel retinoic acid metabolism blocking agents (RAMBA) retinamides and synthesis of prodrugs of our clinical candidate, VN/124-1 (now called TOK-001 or Galeterone). These multi-target agents are being tested in a variety of in vitro and in vivo models of human cancers, including breast, prostate and pancreatic cancers and leukemia. Novel compounds of these projects are code named VNLG- compounds

Dr. Puranik Purushottamachar

I am currently a Research Associate in Dr. Vincent Njar’s laboratory. I graduated with a Ph.D. degree in Pharmaceutical Chemistry from the University Institute of Chemical Technology (UICT), Mumbai, India in 2003. Thereafter, I was a Research Chemist at USV ltd., Mumbia, India from 2003 to 2004 and then joined Dr. Njar’s lab in 2005. My current research is focused on the design and synthesis of novel androgen receptor degrading agents (ARDAs) as potential new therapies for all stages of prostate cancer. The new ARDAs are based on the structure of our proprietary clinical candidate, steroidal VN/124-1 (now called TOK-001 or Galeterone). I am also investigating possible development of novel non-steroidal small molecules as ARDAs that are likely to be superior to the steroidal agents. Novel compounds of these projects are code named VNPP- compounds.

Dr. Senthilmurugan Ramalingam

I obtained my Ph.D. degree in Biochemistry from Annamalai University, Chidambaram, India in 2011. After a brief postdoctoral fellowship in the lab of Dr. Takemi Tanaka at Thomas Jefferson University, Philadelphia, I joined Dr. Vincent Njar’s lab in April 2012 as Postdoctoral Fellow, The primary focus of my work is to explore the inhibitory effects of our novel RAMBA retinamides on MAP kinase-interacting serine/threonine-protein kinase (Mnk) activated eIF4E translation initiation and its downstream oncogenic events in in vitro and in vivo models of triple negative and Her-2 overexpressing breast cancers. This research may lead to identification of more effective agents for the treatment of breast cancer.

Dr. Hannah Mbatia

I obtained a Ph.D. in Chemistry from University of Connecticut, in 2012. After a 6-months postdoctoral fellowship with Dr. Fengtian Xue of Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, I joined the Laboratory of Dr. Vincent Njar in July 2012 as Postdoctoral Fellow. My current project is on the rational design and synthesis of novel RAMBA retinamides based on 13-cis retinoic acid scaffold. These novel compounds are envisioned to possess improved drug-like properties and superior anti-cancer activities. These compounds are currently being investigated in a variety of human cancer models by our oncopharmacology research team. Novel compounds of my synthesis projects are code named VNHM- compounds.

Dr. Vidya Ramamurthy

I obtained my Ph.D. degree in Biochemistry from Annamalai University, Chidambaram, India in 2013. Shortly after submitting my thesis in 2012, I joined in the group of Dr. Vincent Njar as a Postdoctoral Fellow wherein I started investigating the ability of proprietary RAMBA retinamides to modulate androgen receptor (AR), eIF4E translational machinery, nuclear factor kappa B (NF-¿B) and phosphoinositide 3-kinase- protein kinase B- mammalian target of rapamycin (PI3K/Akt/mTOR) pathways- the major oncogenic drivers in advanced prostate cancer in various in vitro and in vivo models of prostate cancer. My work also explores the effects of RAMBA retinamides on cell proliferation and survival, apoptosis, epithelial mesenchymal transition and invasion, the principal events activated by these signaling pathways in prostate cancer cells and castration-resistant prostate cancer (CRPC) xenograft mouse models.

Andrew Kenneth Kwegyir-Afful

I graduated with an M.S. degree in Pharmacology and Experimental Therapeutics in 2009 from University of Maryland, Baltimore. I have been a Graduate Student in Dr. Vincent Njar’s lab since August 2012. I am also a Ph.D. Candidate in the Molecular Toxicology Program. Our lab focuses on anti-cancer small molecules drug discovery and development and is also interested in understanding the mechanisms of action of the proprietary molecules. My current project is to determine the mechanism of how drug-candidate Galeterone (VN/124-1; TOK-001; 3β-hydroxy-17-(1H-benzimidazol-1-yl) androsta-5, 16-diene) and its novel analog VNPT55 enhance the depletion of full length androgen receptor and splice variants AR-V7 (AR3) and ARv567es  in prostate cancer lines. In another project, I am Investigating the effects of our novel ARDAs on specific anti-apoptotic proteins, metastatic inhibitory activities, multi-drug resistance proteins and cell cycle promoting kinases. Inhibition of cellular migration and invasion in vitro and tumor prevention in vivo. I am also investigating the effects and mechanisms of action of our lead ARDAs and RAMBA retinamides (RRs) in models of pancreatic cancer. On May 12, 2014, I successfully defended my Ph.D. thesis proposal.

David McCarty

I received a B.S. degree in Biomedical Sciences from Saint Cloud State University in 2009. I have been working in Dr. Njar’s lab since May 2012 as a Graduate Student. I am also a Ph.D. Candidate in the Molecular Medicine Program. The androgen receptor (AR) has an important role in the development and progression of prostate cancer (PCa) and continues to be active in treatment-resistant stages known as castration resistant prostate cancer (CRPC). Androgen receptor down-modulating agents (ARDAs) are an effective tool in combatting all stages of PCa as they reduce the abundance of the AR protein as well as antagonize its activity. Our lab has developed many novel ARDAs based on the success of our clinical candidate, VN/124-1 which is under license to Tokai Pharmaceuticals and being evaluated in Phase 2 clinical trials in CRPC patients. I am currently characterizing the activity of these novel ARDAs in clinically relevant in vitro models of prostate cancer compared to currently approved pharmaceuticals. The objectives of these studies are to identify structure-function relationships and mechanisms of action that confer a clinical advantage over currently offered therapies, particularly with respect to CRPC

Lena McLaughlin

I obtained a B.S. degree in Biochemistry from University of Washington, Seattle in 2010. After two Research Assistant/Associate positions at University of Washington and Theraclone Sciences, I joined the Graduate Program at University of Maryland, Baltimore in 2012. I joined Dr. Njar’s lab as Graduate Student in October 2013. I am also a Ph.D. Candidate in the Molecular Medicine Program. Breast cancer is one of the most common types of cancer among women (excluding skin). Although there have been many advances in the treatment of breast cancer, such as the antiestrogen tamoxifen and the aromatase inhibitor letrozole, resistance occurs after prolonged treatment. I will be investigating the effects of potential retinoic acid metabolism blocking agents (RAMBAs) on the various drug resistant breast cancer cell lines (MCF7-tamoxifen resistant, long-term letrozole treated MCF-7Ca, and long-term letrozole cultured cell lines compared to their parental MCF7 breast cancer cells). After screening (via MTT assay) and selecting compounds that are promising (based on GI50 values), I will determine if and how common pathways (ERα-HER2/MAPK pathway crosstalks) are affected after treatment with the RAMBAs. I will further establish survival and proliferation capabilities via clonogenic assays and investigate into other pathways that may be affected (MNK, eI4FE) upon RAMBA treatment. The overall goal of the project is to further characterize the inevitable resistance that occurs upon status quo treatments and to determine how RAMBAs are able to combat these resistances and by characterizing their mechanism of action.

Marlena Martin

I obtained a B.S. degree in Pharmacology and Toxicology from University of the Sciences, Philadelphia, Pennsylvania in May of 2010. I joined Dr. Vincent Njar’s lab as a Laboratory Research Technician in October of 2010. Currently, I am testing the the VNHM-1 series of RAMBAs on breast cancer cell lines. The GI50 values have been determined for the compounds tested against the MCF-7, MDA-MB-231, and MDA-MB-468 cell lines. In the next phase, GI50 values will be determined for the SKBR3 cell line. Once these cell viability assays have been completed, a more thorough analysis of the results will be conducted. In another project, I am also evaluating the effects of novel androgen receptor degrading agents (ARDAs) in several prostate cancer cell lines. In addition to these studies, I manage Dr. Njar’s laboratory. I am a prospective Doctor of Pharmacy student. 

Anne Elise R. Drozdoski

In May of 2012, I graduated from Fairfield University in Connecticut with a B.S. in Chemistry and a minor in Mathematics. I currently work as a Laboratory Research Technician in the laboratory of Dr. Vincent Njar, where I am responsible for the synthesis of retinoic acid metabolizing blocking agents (RAMBAs) as anti-cancer agents. These agents are atypical RAMBAs, having beneficial activities apart from inhibiting the metabolism of all-trans retinoic acid (ATRA).

Yong Eun Song

I graduated from Pennsylvania State University, State College, Pennsylvania with a B.S. degree in Microbiology in 2011. I am currently a 2nd year Doctor of Pharmacy Student at University of Maryland School of Pharmacy, Baltimore, MD. As part of PHMY 539 Special Projects, I have been working in the laboratory of Dr. Vincent Njar since June, 2012. My current projects concerns the characterization of prodrugs of clinical candidate VN/124-1 and lead RAMBA retinamides. These studies involve the use of analytical and preparative HPLC and UPLC and NMR techniques.

Yujin Kim

I obtained a B.S. degree in Chemical Biology in 2012 from University of California, Berkeley, CA. I am currently a 1st year Doctor of Pharmacy Student at University of Maryland School of Pharmacy, Baltimore, MD. As part of PHMY 539 Special Projects, I have been working in the laboratory of Dr. Vincent Njar since October, 2013. My current project is on the synthesis and characterization of novel RAMBA retinamides based on 13-cis retinoic acid scaffold.


Former Students and Postdoctoral Fellows/Research Associates

  • Dr. Taiwo Womoloju - (Former Student)
  • Dr. Julius Adesanwo - (Former Student)
  • Dr. Isiaka Oguwande - (Former Student)
  • Dr. Amba Ayambem - (Former Student)
  • Dr. Markus Hector (co-Advisor) - (Former Student)
  • Dr. Carlic Huynh - (Former Student)
  • Dr. Jyoti Patel - (Former Student & Postdoctoral Fellow)
  • Dr. Aashvini Belosay - (Former Postdoctoral Fellow)
  • Dr. Pankaj Chopra (Former Student & Postdoctoral Fellow)
  • Dr. Neha Maheshwari - (Former Postdoctoral Fellow)
  • Dr. Tadas Sean Vasaitis (co-Advisor) - (Former Student)
  • Dr. Vania Moreira (co-Advisor) - (Former Student)
  • Dr. Aakanksha Khandelwal - (Former Student & Postdoctoral Fellow)
  • Dr. Robert Bruno - (Former Student)
  • Dr. Abhijit Godbole - (Former Student& Postdoctoral Fellow)
  • Dr. Bianca Gomez - (Former Postdoctoral Fellow)
  • Dr. Quigyuan Yang - (Former Research Associate)
  • Ms. Jhalak Mehta - (Former Student)

Research Projects:

1. Novel Retinoic Acid Metabolism Blocking Agents (RAMBAs) for Breast and Prostate Cancers.

We have recently designed and synthesized novel inhibitors of all-trans retinoic acid (ATRA) metabolism enzyme (CYP26). These inhibitors are also referred to as retinoic acid metabolism blocking agents (RAMBAs). Some of our compounds are by far the most potent RAMBAs known. These inhibitors may be useful in enhancing the levels of endogenous ATRA, causing ‘ATRA-mimetic’ effects without the need for ATRA administration. Some of our novel RAMBAs are potent inhibitors of growth of both breast and prostate cancer cells and they are also strong inhibitors of breast cancer tumors in animal xenograft models. Our lead multi-target RAMBA, VN/14-1 may be useful for the treatment of endocrine-sensitive and –insensitive breast cancer. Our RAMBAs (VN/14-1) technology has recently been licensed to Cancer Research UK, London, United Kingdom for advanced pre-clinical studies in view of Phase I clinical trials in breast cancer patients.

In both breast and prostate cancer cell lines and tumor xenografts, we have found that combination of our RAMBAs with histone deacetylase inhibitors (HDACIs) result in additive/synergistic cell/tumor growth inhibition. The combination of VN/66-1 and MS-275 is highly effective in both hormone-dependent (LNCaP) and –independent (PC-3) prostate cancer. The technology of/around VN/66-1 will soon be licensed for further development.

Recently, we reported that our RAMBA VN/12-1 induces autophagy and apoptosis and inhibits the growth of SKBR-3 xenografts by 80-90%. We also showed that combination of VN/12-1 with autophagy inhibitor, chloroquine was beneficial. Some of the new projects in the laboratory also involve pharmacological testing our novel RAMBAs against triple-negative breast cancer cell lines and neuroblastoma cell lines. We believe that our RAMBAs have potential to find important application as therapeutic agents in oncology and dermatology. Research on the combination of retinoids and/or RAMBAs with histone deacetylase inhibitors and DNA methylation inhibitors is also being pursued. Another recent interest is to develop new non-retinoidal RAMBAs. In this regard, we developed the first chemical feature-based pharmacophore model of potent retinoidal retinoic acid metabolism blocking agents (RAMBAs), which enabled us to identify novel RAMBAs scaffolds. This new pharmacophore model can now be used for virtual screening of other robust database that should lead to the identification of highly potent RAMBAs with hitherto unknown scaffolds. It is important to note here that our success in the syntheses of new compounds continues to benefit from a novel synthetic method that I invented in 1999, which enables the synthesis of novel C4-azolyl retinoids (see Scheme below; Njar VCO et al., Bioorg. Med Chem. Lett., 2000, 10: 1905-1908).

Ongoing Studies:

On the basis of recent studies, we have determined that our lead compounds, VN/14-1 and its methyl ester, VN/12-1 are fairly toxic in mice. In addition, we have also identified an inactive/toxic polymorph of VN/14-1, following large-scale production. These undesirable activities limit their usefulness. Consequently, we are currently synthesizing novel RAMBA retinamides, which are significantly less toxic than VN/12-1 and VN/14-1. We are exploring the usefulness of these agents in the treatment of breast and prostate cancers. Current projects include rationale design, synthesis and characterization of compounds in attempts to further improve their drug-like properties. Following cell growth inhibition and colony formation assays, lead compounds are subjected to rigorous mechanistic studies to understand how these cancer cells are inhibited. Thereafter, the promising compounds will be tested in appropriate animal xenograft models of breast and prostate cancers. New compounds of this project are code named VNLG-- or VNHM-- compounds.

In recent/ongoing studies, we have discovered that our novel RAMBA Retinamides (RRs) also antagonize transactivation of the androgen receptor (AR), degrade the full-length and splice variant ARs in human prostate cancer cell lines. In addition, the RRs exquisitely cause degradation of MAP kinase-interacting kinases (Mnk 1 and 2) with concomitant blockade of eukaryotic translation initiation factor 4E (eIF4E) cap dependent translation initiation in both human breast and prostate cancer cell lines. Altogether, these effects of RRs in breast and prostate cancer cell lines promotes apoptosis, impede cell growth, cell proliferation and matrix invasion in these cell lines, making the RRs strong candidates for development as novel anti-breast/prostate cancer therapeutics. To the best of our knowledge, our RRs are the first MAP kinase-interacting kinases (Mnk 1/2) degrading agents (MNKDAs) known.

2. Inhibitors of Androgen Synthesis (17α-Hydroxylase/17,20-lyase; CYP17) /Anti-androgens/Androgen Receptor Down-regulating Agents.

In collaboration with Dr. Angela Brodie, we have developed some of the most potent inhibitors of CYP17 known. Some of these novel CYP17 inhibitors are also potent androgen receptor (AR) antagonists (anti-androgens) and cause strong AR degradation. Our lead VN/124-1 is more effective than castration or clinically used antiandrogen (bicalutamide) in suppressing tumor growth and also in preventing their development in LAPC-4 human prostate cancer model. We recently discovered that a clinically used HDACI, vorinostat (SAHA) acts synergistically with VN/124-1 to inhibit AR+ androgen-sensitive and –insensitive LNCaP prostate cancer cell proliferation. Quite unexpectedly, VN/124-1 strongly inhibits proliferation of AR- PC-3 prostate cancer cells. Subsequent mechanistic studies lead to the identification of induction endoplasmic reticulum (ER) stress response as its other mechanism of action. So far, VN/124-1 has at least 4 mechanisms of action, including: CYP17 inhibition, AR antagonism, AR degradation and induction of ER stress response as depicted below.

Our CYP17/antiandrogen technology was licensed to Tokai Pharmaceuticals, Inc. Cambridge, MA in 2006 with the goal of evaluating the impact of VN/124-1 in patients with prostate cancer. Indeed, VN/124-1 (TOK-001 or Galeterone) has recently successfully completed phase I/II clinical trials in castration-resistant prostate cancer patients. On June 12, 2012 Galeterone received Fast Track designation from the U.S. Food and Drug Administration (FDA) for the potential treatment of metastatic castration-resistant prostate cancer (CRPC). Large phase II clinical trials in CRPC patients started on December 17, 2012. Here again, as with the RAMBAs projects, our success in the syntheses of new compounds continues to benefit from a novel synthetic method that I invented in 1996, which enables the synthesis of novel C17-benzimidazole  (see Scheme below; Njar VCO et al., Bioorg. Med Chem. Lett., 1996, 6: 2777-2782; Njar VCO et al., J. Med. Chem., 1998, 41: 902-912).

Ongoing Studies:

In this project our current focus is to use VN/124-1 as a lead to develop a novel class of AR down-regulating agents (ARDAS) through lead optimization and molecular modeling or computer aided drug design strategies. In addition, structural studies and solving X-ray crystal structures of AR in the presence and absence of VN/124-1 and new analogs as well as structural NMR studies are in progress. In this effort, we have an abstract, a manuscript (Purushottamachar P et al., J. Med. Chem., 2013, 56: 4880-4898. Figure 5D of this article was the cover page of August 8, 2013, Volume 56, Number 15 of Journal of Medicinal Chemistry; Pictured right) and two provisional US patent applications that reports on the discovery of VN/124-1 analogs that are ~ 10-fold more potent than VN/124-1. We have also discovered that some of our new ARDAs bind only weakly to the ligand binding domain (LBD) of AR, but they effectively antagonize transactivation of the androgen receptor (AR), and strongly degrade the full-length and splice variant ARs (AR3/AR-V7 and ARV567es) in human prostate cancer cell lines. We are also investigation the mechanism of VN/124-1/new analogs/mimetics-induced AR degradation. The promising compounds will be tested in appropriate animal models of castration resistance prostate cancer and PC metastasis. New compounds of this project are code named VNLG-- or VNPP-- compounds.

Clinical Study Update:

New Phase 2 clinical data on Galeterone (molecular structure pictured right) in advanced prostate cancer was recently presented (January 30, 2014) at 2014 American Society of Clinical Oncology Genitourinary Cancer Symposium (ASCO GU) in San Francisco.

[DATA SUMMARY: The ongoing ARMOR2 trial is a two-part Phase 2 study designed to confirm the dose of reformulated galeterone (Part 1) and demonstrate safety and efficacy in four distinct CRPC patient cohorts (Part 2). Approximately 136 patients are expected to be enrolled in the study. At the conclusion of Part 1 of the study, a once-daily galeterone dose of 2550 mg was selected for Part 2 based upon review of safety, efficacy and pharmacokinetic data. Interim data shows that for 39 patients followed for at least 12 weeks across all doses, 79% achieved a PSA decline of at least 30% (PSA30) and 67% achieved a PSA decline of at least 50% (PSA50). The most mature dataset is in metastatic treatment naïve CRPC where interim data in 21 patients show 90% achieved a PSA30 and 81% achieved a PSA50. In addition, initial data in abiraterone refractory patients shows both biochemical activity and stable disease.]

Based on clinical results to date, Tokai believes that galeterone represents a promising potential new treatment option for CRPC patients and plans are underway to advance galeterone into late-stage (Phase 3) clinical development later this year (2014). I was recently invited to write a Drug Annotation Manuscript on Galeterone (telling the drug discovery story) for publication in Journal of Medicinal Chemistry.


Publications, Patents & Intellectual Properties
Selected Recent Publications

Njar VCO, Safi E, Silverton JV, Robinson CH. Novel 10β-aziridinyl steroids; inhibitors of aromatase. J. Chem Soc. Perkin Trans. 1. 1993:1161-1168.

Akhtar M, Njar VCO, Wright JN. Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes. J. Steroid Biochem. Molec. Biol., 1993, 44:375-387.

Njar VCO, Hector M, Hartmann RW. 20-Amino and 20,21-aziridinyl pregnane steroids: Development of potent inhibitors of 17α-hydroxylase/C17,20-lyase (P-45017α). Bioorg. Med. Chem., 1996, 61:1447-1453.

Njar VCO*, #, Klus GT, Brodie AMH. Nucleophilic vinylic “addition-elimination” substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene: A novel and general route to 17-substituted-¿16 steroids. Part 1. Synthesis of novel 17-azolyl-¿16 steroids; inhibitors of 17α-hydroxylase/17,20-lyase (17α-lyase). Bioorg. Med. Chem. Lett., 1996, 6:2777-2782.

Njar VCO, Kato K, Nnane IP, Grigoryev DN, Long BJ, Brodie, A. M. H. Novel 17-azolyl steroids; potent inhibitors of cytochrome 17α-hydroxylase/17,20-lyase (P45017α): Potential agents for the treatment of prostate cancer. J. Med. Chem., 1998, 41:902-912.

Njar VCO*, #, Nnane IP, Brodie AMH. Potent inhibition of retinoic acid metabolism enzyme(s) by novel azolyl retinoids. Bioorg. Med. Chem. Lett., 2000, 10:1905-1908.

Njar V. C. O*, #. High-yield synthesis of novel imidazoles and triazoles from alcohols and phenols. Synthesis, 2000, 14:2019-2028.

Patel J, Huynh C, Handratta VD, Gediya LK, Brodie AMH, Goloubeva OG, Clement OO, Nnane IP, Soprano DR, Njar VCO. Novel Retinoic Acid Metabolism Blocking Agents (RAMBAs) Endowed with Multiple Biological Activities Are Efficient Growth Inhibitors of Human Breast and Prostate Cancer Cells In Vitro and a Human Breast Tumor Xenograft in Nude Mice. J. Med. Chem., 2004, 47:6716-6729.

Handratta VD, Vasaitis TS, Njar VCO#, Kataria R, Chopra P, Newman Jr. D, Farquhar, R, Brodie AMH.# Novel C-17-Heteroaryl Steroidal CYP17 Inhibitors/Antiandrogens: Synthesis, Pharmacokinetics and Antitumor Activity in the LAPC4 Human Prostate Cancer Xenograft Model. J. Med. Chem., 2005, 48:2972-2984.

Gediya LK, Chopra P, Purushottamachar P, Njar VCO. A New simple and high-yield synthesis of Suberoylanilide Hydroxamic Acid (SAHA) and Its Inhibitory Effect alone or in Combination with Retinoids on Proliferation of Human LNCaP Prostate Cancer Cells. J. Med. Chem., 2005, 48:5047-5051.

Huynh CK, Brodie AMH, Njar VCO. Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumor xenografts in SCID mice. Br. J. Cancer, 2006, 94:513-523.

**Njar VCO*, #, Gediya L, Purushottamachar P, Chopra P, Vasaitis TS, Khandelwal A, Mehta J, Huynh C, Belosay A, Patel J. Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatological diseases. Bioorg. Med. Chem., 2006, 14:4323-4340.

**(1. This review article that appeared on July 1, 2006, was recognized as a “top-25 most downloaded” article from Bioorganic & Medicinal Chemistry (BMC) on ScienceDirect during 2006. 2. Recently, this article has been recognized in the “top-50 most cited article” as published in Bioorganic & Medicinal Chemistry 2005-2008). 3. This paper was recognized as a Best Paper 2006-2009.

Njar VCO*, #, Gediya L, Purushottamachar P, Chopra P, Belosay A, Patel J. Retinoids in clinical use. Med. Chem., 2006, 2:431-438.

Guo Z., Dai B, Jiang T, Xu K, Xie Y, Kim O, Nesheiwat I, Kong X, Melamed J, Handratta VD, Njar VCO, Brodie AMH, Yu L-R, Veenstra TD, Chen H, Qiu Y. Regulation of the androgen receptor activity by tyrosine phosphorylation. Cancer Cell, 2006, 10:309-319.

Belosay A, Brodie AMH, Njar VCO. Effects of novel retinoic acid metabolism blocking agent (VN/14-1) letrozole insensitive breast cancer cells. Cancer Res., 2006, 66:11485-11493.

Patel JB, Khandelwal A, Handratta VD, Chopra P, Njar VCO. Murine toxicology and pharmacokinetics of novel retinoic acid metabolism blocking agents (RAMBAs). Cancer Chemother. Pharmacol., 2007, 60:899-905.

Patel JB, Mehta J, Belosay A, Sabnis G, Khandelwal A, Brodie AMH, Soprano DR, Njar VCO. Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cell and tumor growth. Br. J. Cancer, 2007, 96:1204-1215.

Purushottamachar P, Khandelwal A, Chopra P, Maheshwari N, Gediya LK, Vasaitis TS, Bruno RD, Clement OO, Njar VCO. First pharmacophore-based identification of androgen receptor down-regulating agents: discovery of potent anti-prostate cancer agents. Bioorg. Med. Chem., 2007, 15:3413-3421.

**Bruno RD, Njar VCO. Targeting cytochrome P450 enzymes: A new approach in anti-cancer drug development. Bioorg. Med. Chem., 2007, 15:5047-5060.

** This paper was recognized as a Best Paper 2006-2009.

Lopes C, Pereira EFR, Wu H-U, Purushottamachar P, Njar VCO, Schwarcz R, Albuquerque EX. Competitive Antagonism between the Nicotinic Allosteric Potentiating Ligand Galantamine and Kynurenic Acid at {alpha}7* Nicotinic Receptors. Pharmacol. Exp. Ther., 2007, 322:48-58.

Moreira VMA, Vasaitis TS, Njar VCO#, Salvador JAR.# Synthesis and evaluation of novel 17-indazole androstene derivatives designed as CYP17 inhibitors. Steroids, 2007, 72:939-948.

Gediya LK, Belosay A, Khandelwal A, Purushottamachar P, Njar VCO. Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts. Bioog. Med. Chem., 2008, 16:3352-3360.

Schayowitz A, Sabnis G, Njar VCO, Brodie AMH. Synergistic effect of a novel antiandrogen, VN/124-1 and signal transduction inhibitors in prostate cancer progression to hormone independence in vitro. Mol. Cancer Ther., 2008, 7:121-132.

Purushottamachar P, Khandelwal A, Vasaitis TS, Bruno RD, Gediya LK, Njar VCO. Potent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent. Bioog. Med. Chem., 2008, 16:3519-3529.

Khandelwal A, Gediya LK, Njar VCO. MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumors. Br. J. Cancer 2008, 98:1234-1243.

Moreira VM, Salvador JAR#, Vasaitis TS, Njar VCO#. CYP17 inhibitors for prostate cancer treatment – An update. Curr. Med. Chem., 2008, 15:868-899.

Vasaitis TS, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK, Guo Z, Fang H-B, Njar VCO#, Brodie AMH.# Androgen receptor inactivation contributes to antitumor efficacy of CYP17 inhibitor VN/124-1 in prostate cancer. Mol. Cancer Ther., 2008, 7:2348-2357.

Gediya LK, Khandelwal A, Patel JB, Belosay A, Sabnis G, Mehta J, Purushottamachar P, Njar VCO. Design, synthesis and evaluation of novel mutual prodrugs (hybrid drugs) of all-trans retinoic acid and histone deacetylase inhibitors with enhanced anticancer activities in breast and prostate cancer cells in vitro. J. Med. Chem., 2008, 51:3895-3904.

Moreira VMA, Vasaitis TS, Njar VCO#, Salvador JAR#. Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth. Steroids, 2008, 73:1217-1227.

Bruno RD, Gover TD, Burger AM, Brodie A, Njar VCO. 17α-Hydroxylase/17,20-lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response. Mol. Cancer Ther., 2008, 7:2828-2836.

Njar VCO. Retinoids in clinical use. In: “Nuclear Receptors as Drug Targets”, E. Ottow and H. Weinmann (Eds.), WILEY-VCH Veriag & Co. KGaA, Weinheim, 2008, volume 39, chapter 12, 389-408.

Brodie A, Njar V, Macedo LF, Vasaitis TS, Sabnis G. The Coffey Lecture: Steroidogenic enzyme inhibitors and hormone dependent cancer. Urol. Oncol., 2009, 27:53-63.

Dexheimer TS, Gediya LK, Stephen AG, Weidlich I, Antony S, Marchand C, Interhal H, Nickaus M, Fisher RJ, Njar VC, Pommier Y. 4-Pregnen-21-ol-3,20-dione-21-(4-bromobenzenesufonate) (NSC 88915) and related novel steroid derivatives as tyrosyl-DNA phosphodiesterase (Tdp1) inhibitor. J. Med. Chem., 2009, 52:7122-7131.

Gediya LK, Njar VCO. Promise and challenges in drug discovery and development of hybrid anticancer drugs. Expert Opin. Drug Discov., 2009, 4:1099-1111.

Vasaitis TS, Njar VCO. A review of novel, potent antiandrogens of therapeutic potential: recent advances and promising developments. Future Medicinal Chemistry, 2010, 2:667-680.

Swanson HI, Njar VCO, Yu Z, Castro DJ, Gonzalez FJ, Williams DE, Haug Y, Kong AT, Doloff JC, Ma J, Waxman DJ, Scott EE. Targeting drug-metabolizing enzymes for effective chemoprevention. Drug Metab Dispos., 2010, 38:539-544.

Schayowitz A, Sabnis G, Goloubeva O, Njar VCO#, Brodie AMH.# Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR. Br. J. Cancer, 2010, 103:1001-1007.

**Vasaitis TS, Bruno RD; Njar VCO. CYP17 inhibitors for prostate cancer therapy. J. Steroid Biochem. Mol. Biol., 2011, 125:23-31.

** This paper was recognized as a Top 25 Hottest Article, January to December, 2012 full year.

**Bruno RD, Vasaitis TS, Gediya LK, Purushottamachar P, Godbole AM, Ates-Alagoz, Z, Brodie AMH, Njar VCO. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001) analogs: Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model. Steroids, 2011, 76:1268-1279.

** This paper was recognized as a Top 25 Hottest Article, April to June, 2012.

Godbole AM, Njar VCO. New insights into androgen targeted therapies and epigenetic therapies in prostate cancer. Prostate Cancer, 2011, Article ID 918707,13 pages, doi:10.1155/2011/918707

Godbole AM, Njar VCO. Prostate Cancer: Current and emerging therapies, Current Cancer Treatments – Novel Beyond Conventional Approaches, Oner Ozdemir (Ed) (ISBN 978-953-307-397-2) Available from: July 2011

Goss PE., Qi S, Hu H, Gediya LK., Purushottamachar P, Godbole AM., Njar VCO. Anti-tumor effects of a novel retinoic acid metabolism blocking agent VN/14-1 in the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model and its effects on the uterus. Breast Cancer Res. Treat., 2012, 133: 137-144.

Purushottamachar P, Patel JB, Gediya LK, Clement OO, Njar VC. First chemical feature-based pharmacophore modeling of potent retinoidal retinoic acid metabolism blocking agents (RAMBAs): Identification of novel RAMBA scaffolds. Eur J Med Chem. 2012, 47: 412-423.

Godbole AM, Purushottamachar P, Martin MS, Daskalakis C, Njar VC. Autophagy inhibition synergistically enhances anticancer efficacy of RAMBA, VN/12-1 in SKBR-3 cells, and tumor xenografts. Mol Cancer Ther. 2012, 11: 898-908.

Godbole AM, Purushottamachar P, Martin MS, Njar VC. Murine toxicology and pharmacokinetics evaluation of retinoic acid metabolism blocking agent (RAMBA), VN/12-1. Cancer Chemother Pharmacol. 2012, 70: 339-344

Purushottamachar P, Njar VC. A new simple and high-yield synthesis of 5α-dihydrotestosterone (DHT), a potent androgen receptor agonist. Steroids, 2012; 77: 1530-1534. PMID: 23044354.

Tran K, Risingsong R, B Royce D, Williams CR, Sporn MB, Pioli PA, Gediya LK, Njar VC, Liby KT. The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer. Carcinogenesis, 2013, 34:199-210. PMID: 23042302.

Ramalingam S, Godbole AM, Njar VCO. Modulation of intracellular signaling circuits by dietary food constituents: facts and fantasies for cancer prevention and therapy. In: Food as Medicine. Essa MM, Memon MA (eds); New York. Nova Science Publishers, Inc. 2013, 375-390.

Godbole AM, , Njar VCO. In: Food as Medicine.

**Purushottamachar P, Godbole AM, Gediya LK, Marlena S. Martin MS, Vasaitis TS, Kwegyir-Afful AK, Ates-Alagoz Z, Njar VCO. Systematic Structure Modifications of Multi-target Prostate Cancer Drug Candidate Galeterone to Produce Novel Androgen Receptor Down-regulating Agents as an Approach to Treatment of Advanced Prostate Cancer. J. Med. Chem., 2013, 56: 4880-4898.

** Figure 5D of this article was the cover page of August 8, 2013, Volume 56, Number 15 of Journal of Medicinal Chemistry (The most frequently cited Medicinal Chemistry Journal in the World).

Ramalingam S., Gediya LK, Kwegyir-Afful AK, Purushottamachar P., Vidya P. Ramamurth VP, Mbatia M, and Njar VCO. First MAP Kinase Interacting Kinase 1 Degrading Agents Block Phosphorylation eIF4E, Induce Apoptosis, Inhibit Cell Growth, Migration and Invasion in Triple Negative and HER2-overexpressing Breast Cancer Cell Lines. Oncotarget, 2014, 5: 530-543.

Godbole AM, Ramalingam S., Ramamurthy VP, Khandelwal A, Bruno RD, Upreti VV, Gediya LK, Purushottamachar P, Ramalingm S, Mbatia HW, Addya S, Ambulos N, Njar VCO. VN/14-1 induces ER stress and autophagy in HP-LTLC human breast cancer cells and has excellent oral pharmacokinetic profile in female Sprague Dawley rats. Eur. J. Pharmacol., 2014, 734: 98-104.

Selected Patents & Intellectual Properties (Inventions and Licenses)

Dr. Vincent Njar holds fourteen patents from the US and several other countries and has forty one active Intellectual Property and Licensing Activities as of January 3, 2014 with University of Maryland, Baltimore Office of Research and Development.