Learning From Estrogen Receptor Antagonism: Structure‐Based Identification of Novel Antiandrogens Effective Against Multiple Clinically Relevant Androgen Receptor Mutants

Abstract

Current treatment strategy for advanced prostate cancer is to suppress androgen receptor (AR) by castration and antiandrogens. However, several clinically relevant AR mutations cause insensitivity to current antiandrogens and convert them into agonists. We aim to identify full AR antagonists even for AR mutants. As crystal structure of AR ligand-binding domain (LBD) at antagonistic form is not available, we decided to learn from estrogen receptor (ER) antagonism: (i) We built a structural model of wild-type AR-LBD complexed with antiandrogen bicalutamide (wild type ⁄ bicalutamide) using ERa-LBD ⁄ hydroxytamoxifen structure as the template for helix-12.(ii) By comparative structural analysis of 24 ERa-LBD complexes, we found residues D351 and L354 at helix-3 adopt unique conformations, and distance between them is a marker of ERa-LBD ⁄ antagonist complexes. The AR residues corresponding to D351 and L354 are E709 and L712, respectively. We found distance between E709 and L712 of the wild type⁄ bicalutamide model is substantially different from that of AR-LBD ⁄ agonist complexes, suggesting this distance could be a marker of antagonistic AR-LBD, which was supported by molecular dynamics simulations. Based on the wild type ⁄ bicalutamide model, we discovered compound 3 is a novel antiandrogen effective against the wild type and T877A-, W741C-, and H874Y-mutated androgen receptors. We found compound 3 has dual functions, inhibiting androgen receptor and IKK b .

Androgen receptor: structure, role in prostate cancer and drug discovery

“…Interestingly, these compounds also impair nuclear localization and enhance AR degradation, thus providing a multi-pronged approach that might overcome all new somatic mutations that arise during the course of the disease 199 . Other candidates, such as compound 3 from the NCI-3D database 200 , DIMN analogs termed 7AU and 7BB 201 , and MEL-3 202 , all showed encouraging in vitro activities and need to be tested in animal models.…”

Androgen receptor mutations for precision medicine in prostate cancer

“…Taken together, the clinical relevance of AR mutants including L702H, W742L, W742C, H875Y, F877L, T878A, and T878S has been demonstrated, as cBioPortal currently defines these mutants as driver missense mutations. However, since high-level evidence on clinical implications Several studies indicate sensitivity (Taplin et al 1999, Urushibara et al 2007, Tran et al 2009, van de Wijngaart et al 2010, Terada et al 2010, Clegg et al 2012, Liu et al 2012; †Preferred agent (Romero-Laorden et al…”

Discovery and Identification of Pyrazolopyramidine Analogs as Novel Potent Androgen Receptor Antagonists

“…Taking into account that the crystal structure of AR with antagonistic manner (Anti-AR) is unclear, homology modeling was applied to construct its Anti-AR conformation using the same method as previously reported (Liu et al, 2012). Then the AR crystal structure (PDB ID:1T65) and Anti-AR were both used to virtually screen the ChemDiv database by using Glide standard precision (SP) docking program.…”

“…All other adjustable settings were set as default. Moreover, we constructed an antagonistic AR (named Anti-AR) model according to the reported homology modeling methodology (Liu et al, 2012). …”

“…Considering the published AR protein crystal structures are all in the agonistic manner (Bohl et al, 2005a,b), we firstly constructed its antagonistic conformation by using homology modeling according to the reported process (Liu et al, 2012). Structure-based docking method was used to find out chemicals that could bind to AR with high affinities.…”