Perspectives on designs of antiandrogens for prostate cancer

Abstract

The androgen receptor (AR) regulates gene transcription in many tissues and is profoundly important in prostate cancer. Antiandrogens compete with the natural hormone and are front line therapeutics to treat prostate cancer. However, antiandrogens frequently become ineffective after prolonged treatment because of development of tumor resistance. This paper reviews design principles for new generations of antiandrogens: super antagonists and surface allosteric modulators. Super antiandrogens are compounds with higher binding affinity than natural agonists and that contain precisely engineered hydrophobic groups that disrupt AR function. AR surface is also an attractive alternative target. Surface inhibitors are small molecules that directly block the receptor-co-activator interface, preventing co-activator recruitment. The challenges to designing these compounds are significant but so is the potential for treatment of the disease.

Role of steroid receptor and coregulator mutations in hormone-dependent cancers

“…Consistently, multiple ER coactivators were recruited to the ER mutant AF-2 in a ligandindependent manner. In PCa patients with AR gain-of-function LBD mutations, AR is transcriptionally active because mutations such as T878A and W742L result in an antagonist-bound activating conformation, where helix 12 is in the agonistic state (67). Promiscuous activity of ligands, such as glucocorticoids on the L702H mutation, may be explained structurally by the fact that residues within the ligand-binding pocket not only determine the structure of the LBD, but also dictate the types of ligands that can be accommodated (68).…”

Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

“…More than 300 proteins that exhibit AR coactivator or corepressor properties have been identified [42,43]. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective even in instances where currently used AR antagonists fail [17,[44][45][46][47].…”

Beyond the Ligand-Binding Pocket: Targeting Alternate Sites in Nuclear Receptors

“…Current LBP drug discovery strategy is based on the design of “super” antagonists and modulators with superior potency than the natural ligands or on the design of “pure” antagonists that lack intrinsic agonist activity and bear tissue selective properties. Examples include enzalutamide (MDV3100), which demonstrates effectiveness in castration‐resistant prostate cancer (CRPC) in phase III clinical trials, and the pure antiestrogen fulvestrant (ICI 182,780), an FDA‐approved drug for metastatic breast cancer …”

“…This approach is believed to overcome traditional LBP drug resistance issues by direct blockade of NR transcriptional activation. It is predicted that this interface would have lower incidence of adaptive mutations compared to the LBP, as any mutations at the NR‐cofactor interface that renders the drug ineffective would also block the cofactor recruitment …”

“…It is predicted that this interface would have lower incidence of adaptive mutations compared to the LBP, as any mutations at the NR-cofactor interface that renders the drug ineffective would also block the cofactor recruitment. 10 Interestingly, instead of looking at the NR-protein interface to block coregulator recruitment, direct coactivator inhibition with small molecules was also recently explored. 37 As coactivator overexpression is believed to be one of the hallmarks of drug resistance, this strategy would offer several advantages, such as the possibility of tailoring each inhibitor for a specific coactivator.…”