Development of new inhibitors of androgen receptors

Gurova, Katerina

Abstract

This program is aimed at developing a new class of drugs effective against most aggressive and a poorly curable hormone independent form of prostate cancer (CAP). Failure of androgen ablation therapy is rarely associated with the loss of the androgen receptor (AR) signaling by hormone-independent CaP. AR pathway in such tumors remains constitutively active regardless of the presence of the hormone, indicating that the tumor remains dependent on the AR pathway activity. So far anti-androgen therapy of CaP has been focused predominantly on the abrogation of AR-hormone interaction but not on the AR-mediated transcription per se. Thus AR-mediated transactivation can be considered as a potential target for pharmacological inhibition in both androgen-dependent and independent prostate cancer. Genetic evidence was generated in support of this idea indicating that suppression of AR function can cause killing effect on hormone-independent CaP. The goals of the fist stage of this program described in this proposal involve creation and testing cell-based readout systems suitable for screening compounds with therapeutic activity against androgen-independent prostate cancer (Phase I). The next stage is to develop in vivo validated leads that would form a set of prospective candidate drugs useful to cure hormone-independent CaP (Phase II). The program is based on the integration efforts of two collaborating parties: The Cleveland Clinic Foundation (CCF) and Cleveland BioLabs, Inc. (CBL). Expertise in medicinal chemistry and lead optimization capabilities are provided by ChemBridge Corporation, a leading manufacturer of chemical libraries.