Development of VNPP433-3Beta as Novel Therapeutic for All Stages of Prostrate Cancer

Project Title: Development of VNPP433-3β as Novel Therapeutic for All Stages of Prostate Cancer PROJECT SUMMARY/ABSTRACT Currently, there are no FDA-approved prostate cancer (PC) drugs that inhibit both tumor growth and metastasis from the primary tumor and the metastatic sites. It is now well-established that blocking a single pathway is often ineffective against aggressive solid tumors/metastasis due to feedback and activation of alternative pathways. We have recently shown that proprietary Isoprene Pharmaceuticals Inc. (IPI) and our lead Next Generation Galeterone Analogs (NGGA), VNPP433-3β (3β), with three back-up compounds [3β.HCl (VNPP548) and 3β.diHCl (VNPP595), and VNPP414] simultaneously target both f-AR/AR-V7 and Mnk1/2-eIF4E signaling pathways are efficacious against both bulk PC tumor cell and PC stem cells. Remarkably, when 3β was converted its mono- and di-hydrochloride salts, they exhibit enhanced aqueous solubility and anti-PC in vitro and in vivo potencies by 4-fold against difficult-to-treat CWR22Rv1 tumor xenografts with no apparent host toxicity and were highly more efficacious than the blockbuster FDA-approved prostate cancer drugs, Enzalutamide (Xtandi, ENZ) and Docetaxel (Taxotere, DXT). 3β is an orally bioavailable molecular glue degrader as it induces ubiquitin-mediated proteasomal degradation of f-AR/AR-Vs and Mnk1/2, resulting in potent inhibition of these critical oncogenic pathways. This results in strong modulation of downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Indeed, our compounds exhibit potent PC inhibition by reducing the expression of several oncogenes, while increasing protein levels of several tumor suppressors, including p53, with no apparent host toxicity. Collectively, these studies demonstrate that targeting f-AR/AR-Vs and Mnk1/2- eIF4E signaling with orally bioavailable 3β/salts is a novel therapeutic strategy that can be developed as monotherapy for the effective treatment of patients with both primary and metastatic PC. With support from internal/other funds (NIH/NCI R01 CA224696), we have successfully completed all the aims of our SBIR Phase-1-type R&D study as well as conducted many additional studies that were not originally anticipated. We are now seeking Direct-to-Phase II SBIR support to advance 3β. through various Investigational New Drug (IND)-enabling pre-clinical development activities. Our goal is to develop 3β as an oral targeted anticancer agent for effective treatment of the difficult-to-treat primary and metastatic PC. The specific aims for this Direct-to-Phase II SBIR proposal are: 1. Synthesize 500 g of non-GMP 3β for preclinical studies, including analytical characterization, selection of suitable salt form, formulation and use this agent to support GLP preclinical studies. 2. Conduct ancillary pharmacology with 3β using in vitro and in vivo models of PC. 3. Conduct IND-enabling studies, including GLP toxicity and toxicokinetics studies in two relevant animal species to identify appropriate starting 3β dose for use in first-in-human Phase I clinical trials and prepare the IND filing. Upon successful completion of these studies an FDA Investigational New Drug (IND) application will be filed.