Background

Among different types of cancers, prostate cancer (PCa) is the third most commonly diagnosed tumor around the world, ranking first in incidence among men and second leading cause of cancer death in this gender.

Prostate cancer pathology has started to be understood at the molecular level. Normal development and function of prostate strongly depend on the action of both, androgen and androgen receptor (AR). Most tumors exhibit AR gene amplification and/or somatic prostate mutations and can be treated with drugs such as Enzalutamide /Xtandi which targets AR. However, there are around 20% of PCa cases that lack AR (AR-neg) and for these patients there are no treatments. In fact, patients treated with AR inhibitors such as Enzalutamide /Xtandi develop resistance over time and there are no alternatives. Hence there is a need to develop new treatments for PCa that differs from targeting AR and rely on a different mechanism.

As shown in , the CBX7 protein of the polycomb repressive complex 1 (PRC1) functions to repress transcription of tumor suppressor p16^INK4a through long noncoding RNA, ANRIL (antisense noncoding RNA in the INK4 locus) directed chromodomain (ChD) binding to trimethylated lysine 27 of histone H3 (H3K27me3), resulting in chromatin compaction at the INK4a/ARF locus.

Technology Overview

This invention describes a class of novel bicyclic small molecule inhibitors of the chromobox 7 (CBX7) protein of the polycomb repressive complex (PRC1) that functions as a repressor to the tumor suppressor p16^INK4a. Elevated levels of CBX7 are directly correlated to decreased levels of p16^INK4a in prostate cancer cells as compared to normal prostate cells whose transcriptional repression is controlled by the polycomb repressive complexes PRC1 and PRC2. Therefore, antagonists of CBX7 are a treatment for prostate and potentially other cancers via a unique mechanism.

Mount Sinai researchers have found small molecules that inhibit H3K27me3 binding when CBX7/ChD is bound to RNA. They effectively induce transcriptional de-repression of CBX7 target genes, including p16^INK4a in human AR-neg prostate cancer PC3 cells. Thus, these compounds are a new class of ChD antagonists that selectively targets epigenetic mechanism of prostate cancer.

Stage of Development

Synthesized and tested a novel class of small molecule inhibitors of CBX7
Showed induce transcriptional de-repression of the tumor suppressor p16 in human PCa cells (< 1M)

Benefits

Targets an epigenetic mechanism which is new compared to the state of the art

Applications

Treatment for AR-neg prostate cancer
Treatment for Enzalutamide /Xtandi resistant prostate cancer

First-in-Class Small-Molecule Chemical Antagonists Targeting Epigenetic Protein CBX7 in AR-neg Prostate Cancer