7 research outputs found
Identification of Novel Androgen Receptor Antagonists Using Structure- and Ligand-Based Methods
Androgen receptor (AR) plays a critical role in the development
and progression of prostate cancer (PCa). The AR hormone-binding site
(HBS) is intensively studied and represents the target area for current
antiandrogens including Bicalutamide and structurally related Enzalutamide.
As resistance to antiandrogens invariably emerges in advanced prostate
cancer, there exists a high medical need for the identification and
development of novel AR antagonists of different chemotypes. Given
the wealth of structural information on the AR in complex with a variety
of ligands, we have applied an integrated structure- and ligand-based
virtual screening methodology to identify novel AR antagonists. Virtual
hits generated by a consensus voting approach were experimentally
evaluated and resulted in the discovery of a number of structurally
diverse submicromolar antagonists of the AR. In particular, one identified
compound demonstrated anti-AR potency <i>in vitro</i> that
is comparable to the clinically used Bicalutamide. These results set
a ground for the development of novel classes of PCa drugs that are
structurally different from current AR antagonists
Cheminformatics Modeling of Adverse Drug Responses by Clinically Relevant Mutants of Human Androgen Receptor
The
human androgen receptor (AR) is a ligand-activated transcription factor
that plays a pivotal role in the development and progression of prostate
cancer (PCa). Many forms of castration-resistant prostate cancer (CRPC)
still rely on the AR for survival. Currently used antiandrogens face
clinical limitations as drug resistance develops in patients over
time since they all target the mutation-prone androgen binding site
(ABS), where gain-of-function mutations eventually convert antagonists
into agonists. With a significant number of reported distinct mutations
located across the ABS, it is imperative to develop a prognostic platform
which would equip clinicians with prior knowledge and actionable strategies
if cases of previously unreported AR mutations are encountered. The
goal of this study is to develop a theoretical approach that can predict
such previously unreported AR mutants in response to current treatment
options for PCa. The expected drug response by these mutants has been
modeled using cheminformatics methodology. The corresponding QSAR
pipeline has been created, which extracts key protein–ligand
interactions and quantifies them by 4D molecular descriptors. The
developed models reported with an accuracy reaching 90% and enable
prediction of activation of AR mutants by its native ligand as well
as assess whether known antiandrogens will act on them as agonists
or antagonists. As a result, a previously uncharacterized mutant,
T878G, has been predicted to be activated by the latest antiandrogen
enzalutamide, and the corresponding experimental evaluation confirmed
this prediction. Overall, the developed cheminformatics pipeline provides
useful insights toward understanding the changing genomic landscape
of advanced PCa
Discovery of 1<i>H</i>‑Indole-2-carboxamides as Novel Inhibitors of the Androgen Receptor Binding Function 3 (BF3)
To overcome resistance to conventional
anti-androgens of human
androgen receptor (AR), the allosteric site of the AR binding function
3 (BF3) was investigated as an alternative target for small molecule
therapeutics. A library of 1<i>H-</i>indole-2-carboxamides
were discovered as BF3 inhibitors and exhibited strong antiproliferative
activity against LNCaP and enzalutamide-resistant prostate cancer
cell lines. Several of the lead compounds may prove of particular
benefit as a novel alternative treatment for castration-resistant
prostate cancers
Discovery of Small-Molecule Inhibitors Selectively Targeting the DNA-Binding Domain of the Human Androgen Receptor
The
human androgen receptor (AR) is considered as a master regulator
in the development and progression of prostate cancer (PCa). As resistance
to clinically used anti-AR drugs remains a major challenge for the
treatment of advanced PCa, there is a pressing need for new anti-AR
therapeutic avenues. In this study, we identified a binding site on
the DNA binding domain (DBD) of the receptor and utilized virtual
screening to discover a set of micromolar hits for the target. Through
further exploration of the most potent hit (<b>1</b>), a structural
analogue (<b>6</b>) was identified demonstrating 10-fold improved
anti-AR potency. Further optimization resulted in a more potent synthetic
analogue (<b>25</b>) with anti-AR potency comparable to a newly
FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated
that the developed inhibitors do interact with the intended target
site. Importantly, the AR DBD inhibitors could effectively inhibit
the growth of Enzalutamide-resistant cells as well as block the transcriptional
activity of constitutively active AR splice variants, such as V7
Discovery of Small-Molecule Inhibitors Selectively Targeting the DNA-Binding Domain of the Human Androgen Receptor
The
human androgen receptor (AR) is considered as a master regulator
in the development and progression of prostate cancer (PCa). As resistance
to clinically used anti-AR drugs remains a major challenge for the
treatment of advanced PCa, there is a pressing need for new anti-AR
therapeutic avenues. In this study, we identified a binding site on
the DNA binding domain (DBD) of the receptor and utilized virtual
screening to discover a set of micromolar hits for the target. Through
further exploration of the most potent hit (<b>1</b>), a structural
analogue (<b>6</b>) was identified demonstrating 10-fold improved
anti-AR potency. Further optimization resulted in a more potent synthetic
analogue (<b>25</b>) with anti-AR potency comparable to a newly
FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated
that the developed inhibitors do interact with the intended target
site. Importantly, the AR DBD inhibitors could effectively inhibit
the growth of Enzalutamide-resistant cells as well as block the transcriptional
activity of constitutively active AR splice variants, such as V7
Targeting the Binding Function 3 (BF3) Site of the Androgen Receptor Through Virtual Screening. 2. Development of 2‑((2-phenoxyethyl) thio)‑1<i>H</i>‑benzimidazole Derivatives
The human androgen receptor (AR) is a proven therapeutic
target in prostate cancer. All current antiandrogens, such as Bicalutamide,
Flutamide, Nilutamide, and Enzalutamide, target the buried hydrophobic
androgen binding pocket of this protein. However, effective resistance
mechanisms against these therapeutics exist such as mutations occurring
at the target site. To overcome these limitations, the surface pocket
of the AR called binding function 3 (BF3) was characterized as an
alternative target for small molecule therapeutics. A number of AR
inhibitors directly targeting the BF3 were previously identified by
us (J. Med. Chem. 2011. 54, 8563). In the current study, based on the prior results, we have developed
structure–activity relationships that allowed designing a series
of 2-((2-phenoxyethyl)Âthio)-1<i>H</i>-benzimidazole and
2-((2-phenoxyethyl)Âthio)-1<i>H</i>-indole as lead BF3 inhibitors.
Some of the developed BF3 ligands demonstrated significant antiandrogen
potency against LNCaP and Enzalutamide-resistant prostate cancer cell
lines
Targeting the Binding Function 3 (BF3) Site of the Androgen Receptor Through Virtual Screening. 2. Development of 2‑((2-phenoxyethyl) thio)‑1<i>H</i>‑benzimidazole Derivatives
The human androgen receptor (AR) is a proven therapeutic
target in prostate cancer. All current antiandrogens, such as Bicalutamide,
Flutamide, Nilutamide, and Enzalutamide, target the buried hydrophobic
androgen binding pocket of this protein. However, effective resistance
mechanisms against these therapeutics exist such as mutations occurring
at the target site. To overcome these limitations, the surface pocket
of the AR called binding function 3 (BF3) was characterized as an
alternative target for small molecule therapeutics. A number of AR
inhibitors directly targeting the BF3 were previously identified by
us (J. Med. Chem. 2011. 54, 8563). In the current study, based on the prior results, we have developed
structure–activity relationships that allowed designing a series
of 2-((2-phenoxyethyl)Âthio)-1<i>H</i>-benzimidazole and
2-((2-phenoxyethyl)Âthio)-1<i>H</i>-indole as lead BF3 inhibitors.
Some of the developed BF3 ligands demonstrated significant antiandrogen
potency against LNCaP and Enzalutamide-resistant prostate cancer cell
lines