title: BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients.
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.
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Sugawara
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Pascale
authors.initials: P
authors.lastname: Lejeune
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Köhr
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Hortensia
authors.initials: H
authors.lastname: Faus
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Gelato
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Busemann
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Arwed
authors.initials: A
authors.lastname: Cleve
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lücking
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: von Nussbaum
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Brands
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.affiliation: Berlin Institute of Urologic Research, Berlin, Germany.|Department of Urology, Charité University Hospital, Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.affiliation: Berlin Institute of Urologic Research, Berlin, Germany.|Department of Urology, Charité University Hospital, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Stephan
authors.affiliation: Global Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Bernard
authors.initials: B
authors.lastname: Haendler
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D013867:Thiohydantoins / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D013867:Thiohydantoins
keywords: androgen receptor; anti-androgen resistance; mutant; prostate cancer