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).
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
Former Students and Postdoctoral Fellows/Research Associates
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).
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).
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.