The Silver Lining in BET Protein Targeting for Advanced Prostate Cancer
Pharmacotherapy: Recent Updates
Abstract
Despite advances made over the years in the pharmacotherapy of prostate
cancer, progression to the advanced phenotypes which ultimately account
for the high rate of mortality in patients continue to pose a
significant challenge to clinical management and outcomes. Recent
integrative strategies geared towards the identification of beneficial
molecules have identified the role of epigenetics and in turn BET
proteins in the disease progression. In this review, we explored the
role of BET protein paralogs in prostate tumorigenesis and proceeded to
probe pharmacotherapeutic targeting of BET proteins using small molecule
inhibitors with emphasis on computational techniques employed. Finally,
we explored the relevance of various computational techniques to
uniquely classify bromodomain-containing protein–targeted molecules
with efficacy in advanced prostate cancer. Our opinion is that many
small molecule inhibitors of BET proteins have been identified with some
making it to clinical trials, albeit unsuccessfully. Although several
computer-aided drug design (CADD) techniques have been employed, the
continuous integration of CADD will only serve to improve on efforts
already made towards the design of efficacious, potent, and highly
selective novel BET inhibitors as witnessed recently in the suppression
of treatment-emergent neuroendocrine prostate cancer (NEPC) by BRD4
inhibitors.