BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients

// Tatsuo Sugawara 1 , Pascale Lejeune 1 , Silke Köhr 1 , Roland Neuhaus 1 , Hortensia Faus 1 , Kathy A. Gelato 1 , Matthias Busemann 1 , Arwed Cleve 1 , Ulrich Lücking 1 , Franz von Nussbaum 1 , Michael Brands 1 , Dominik Mumberg 1 , Klaus Jung 2,3 , Carsten Stephan 2,3 and Bernard Haendler 1 1 Global Drug Discovery, Bayer Pharma AG, Berlin, Germany 2 Berlin Institute of Urologic Research, Berlin, Germany 3 Department of Urology, Charité University Hospital, Berlin, Germany Correspondence to: Bernard Haendler, email: // Keywords : prostate cancer, androgen receptor, anti-androgen resistance, mutant Received : October 22, 2015 Accepted : December 24, 2015 Published : January 09, 2016 Abstract Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.