Vincent C.O. Njar, PhD, (UCL/London)

• University of Ibadan, Ibadan, Nigeria, B.Sc. (Hons), Chemistry, 1976
• University of London (University College, London), United Kingdom, Ph.D. Organic Chemistry, 1980
• Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts, USA, Postdoctoral Fellowship, 1980-1982

Dr. Vincent Njar has a long standing interest in the rational discovery and development of small molecules as anti-cancer agents. He is a leading medicinal chemist and oncopharmacologist who has made significant discoveries in the development of novel small molecules with potential for the treatments of a variety of cancers, especially breast, prostate and pancreatic cancers. Dr. Njar invented novel reactions that led to the synthesis 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 and prostate cancer tumors in animal xenograft models.

In ongoing studies, we have discovered that our novel RAMBA retinamides, now called novel retinamides (NRs) 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 NRs 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 NRs in breast and prostate cancer cell lines promotes apoptosis, impede cell growth, cell proliferation and matrix invasion in these cell lines, making the NRs strong candidates for development as novel anti-breast/prostate cancer therapeutics. To the best of our knowledge, our NRs are the first MAP kinase-interacting kinases (Mnk 1/2) degrading agents (MNKDAs) known. Further development of these agents are ongoing in collaboration with Terpene Pharmaceuticals LL, a small business founded by Dr. Njar in 2014.

In collaboration with Angela Brodie, Ph.D., internationally renowned breast cancer researcher, we 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), strong degraders of AR and its splice variants. Our clinical candidate galeterone (gal; formerly called VN/124-1 or TOK-001) successfully advanced through Phase I and II studies (under an exclusive license by University of Maryland, Baltimore (UMB) to Tokai Pharmaceuticals Inc.), showing that gal was well tolerated with promising clinical activity in men with castration resistant prostate cancer (CRCP). Phase III trial, ARMOR3-SV, was launched in which enzalutamide was compared to gal in patients with mCRPC expressing an AR-V7 splice variant, with the primary endpoint being radiographic progression free survival (rPFS). However, a recent interim analysis by the independent Data Monitoring Committee revealed that the primary endpoint was unlikely to be met, and therefore the trial was discontinued, though no safety concerns were cited.

In our efforts to discover and develop the next generation galeterone analogs (NGGAs), we have discovered that gal and the NGGAs degrade Mnk1/2 to disrupt the rate-limiting eukaryotic translational initiation factor 4E (eIF4E) signaling, thus causing inhibition of tumor growth, metastasis and treatment resistance in various cancers. Gratifyingly, the lead NGGAs have superior efficacies and pharmaceutical properties compared to gal.

Medicinal Chemistry, oncopharmacology, anti-cancer drug discovery and development, small-molecule design and synthesis, cancers (breast, prostate, pancrease, skin), steroidal compounds, retinoidal compounds, steroid and retinoid-mimetics, pharmacokinetics, anti-tumor xenograft studies, inhibitors of CYP26, CYP17 and CYP19 (aromatase), AR antagonists, AR/AR-Vs degraders, Mnk1/2 degraders, inhibitors of oncogenic protein translation, Mnk1/2, eukaryotic translation initiation factor 4F/ eukaryotic initiation factor 4E, inhibitors of tumor growth and metastasis, mechanisms of action of anti-cancer agents.

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.

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.