Small molecule inhibitors of steroid receptors for breast and prostate cancer

Steroid hormone receptors play a critical role in the growth and progression of hormone-dependent cancers. This thesis aimed at identifying and characterizing new chemical entities with therapeutic potential in breast and prostate cancer treatment. Reported here are two inhibitors that antagonize androgen receptor (AR) function and one that suppresses estrogen receptor (ER) signaling. Moderate-to-high throughput screens of chemical libraries were designed and implemented to identify these inhibitors. The most promising inhibitor of AR transactivation to have emerged from the rigorous screening process was CPIC (1-(3-(2-chlorophenoxy) propyl)-1H-indole-3-carbonitrile). CPIC is capable of potently and specifically reducing androgen-induced proliferation and gene expression in prostate cancer cells. CPIC also inhibited recruitment of androgen-bound AR to the DNA regulatory sites of target genes in multiple cell lines. CPIC exhibits a mode of action different from that of classical AR antagonists, bicalutamide or flutamide. Additionally, CPIC at nanomolar concentrations, but not bicalutamide, disrupts the amino-carboxyl (N/C) terminal interaction of AR, which is crucial for optimum androgen-mediated AR signaling. Also described here is a novel non-competitive inhibitor of AR action, AR54 (2-(pyrimidin-2-ylthio)-1-(2,2,4-trimethyl-4-phenyl-3,4-dihydroquinolin-1(2H)-yl)ethanone). AR54 blocks prostate cancer cell proliferation by reducing AR mRNA levels and down-regulating AR protein levels. We have not yet determined whether AR54 reduces the production of AR transcripts or increases the rate of mRNA degradation. AR54 modestly inhibits both androgen-dependent and androgen-independent proliferation of 22Rv1 cells, a model for castration-recurrent prostate cancer. These novel small molecule inhibitors represent important new probes for understanding AR action. In addition, CPIC and its structural analogues have properties that make them suitable for further evaluation and development as therapeutics for aggressive late-stage prostate cancers resistant to current therapies.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2012

Author dc:creator

• Cherian, Milu

Contributors dc:contributor

• Shapiro, David J.
• Katzenellenbogen, Benita S.
• Hergenrother, Paul J.
• Bolton, Eric C.

• Androgen receptor
• Prostate cancer
• 1-(3-(2-chlorophenoxy)propyl)-1H-indole-3-carbonitrile (CPIC)
• Drug discovery
• Small molecule
• High throughput screening

Statement dc:rights

• Copyright 2012 Milu Cherian

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/34580

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/34580