TAS::75 0849::TAS TOPIC 255: A NOVEL, NON-COMPETITIVE ANDROGEN RECEPTOR INHIBITOR

The androgen receptor (AR) remains a key therapeutic target for prostate cancer (PCa), even in castration resistant PCa (CRPC). Current therapies target AR by blocking androgen synthesis or competitive antagonism. ARTA Bioscience is developing an early lead, ABS-001, a non-competitive AR inhibitor that is synergistic with competitive antagonists. It blocks ligand-induced conformational change in AR at nanomolar levels in vitro and in vivo, without affecting hormone binding. It is effective against constitutively active AR truncation products that may playa role in CRPC, and AR mutants with reduced sensitivity to competitive antagonists. It has the potential to complement, if not supplant, all existing anti-androgen therapies used for CRPC, and might also be extended as a first line therapy. The grant has three objectives. 1 ) Chemically characterize ABS-001 to determine the activity of each enantiomer; determine solubility and optimal formulation parameters; carry out early pharmacokinetic studies inrodents. 2) Carry out pharmacodynamic studies in rodents to confirm AR inhibitory activity in wild-type mice, and xenograft models of prostate cancer. 3) Characterize ABS-001 in vitro using standard measures of potential cardiotoxicity and mutagenicity. If successful, this compound will be ready for IND-enabling studies to be funded by a Phase II SBIR grant.