# Small Molecules Modulating CBX7 Protein as Potential Anticancer Agents

> **NIH NIH R03** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $84,750

## Abstract

PROJECT SUMMARY
Prostate cancer is the second major cause of cancer death in American men. CBX7 is a Polycomb protein that
participates in the assembly of the Polycomb repressive complex 1 (PRC1). CBX7 when associated with PRC1
has been shown to bind, through its chromodomain (ChD), to histone H3K27me3, a highly conserved
epigenetic mark in all eukaryotes and trigger transcriptional repression of tumor suppressor p16INK4a. Elevated
levels of CBX7 are directly linked to prostate cancer progression. Therefore, small molecules capable of
modulating CBX7ChD-H3K27me3 interaction can serve a powerful research tool to study CBX7 functions in
gene transcriptional regulation in biology and cancer. We have developed the “first-in-class” small molecule
inhibitors for the CBX7ChD. Our lead compound, MS351, is selective for CBX7ChD, and de-represses p16INK4a
in prostate cancer cells through inhibiting CBX7 in its functionally active state. We recently developed novel
MS351 analogs, of which some show much improved binding affinity over MS351. Accordingly, we have
designed new Series I that combines the chemical features of our more potent analogs to develop potent and
selective chemical probes for CBX7. Based on our recent metabolite identification study, we further designed
Series II compounds to systematically block metabolic hotspots, while conserving existing binding, and probing
for additional interactions in the CBX7ChD. Given that MS351 is selective for CBX7, we propose to develop the
MS351-based, first-in-class PROTACs for CBX7 (Series III). Series I-III will be evaluated for target (CBX7ChD)
engagement by the in vitro assays that our group has reported (FP and HSQC assay). In addition, for Series
III, we will determine the cellular activity of these compounds in target protein CBX7 degradation in prostate
cancer cell-lines (PC3). Global levels of CBX7 and other CBX proteins will be analyzed in these cells after
compound treatment at different concentrations by using western blotting. This study will provide an estimate
of potential selective degradation of the target protein CBX7, as well as determine whether CBX7 degradation
by the PROTACS is dose-dependent. Overall, in this study, we will use structure-guided design to develop new
chemical modulators (Series I-III) with improved potency, metabolic stability, and selectivity for CBX7ChD.

## Key facts

- **NIH application ID:** 9876929
- **Project number:** 5R03CA238559-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Nilesh Zaware
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $84,750
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-04-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876929

## Citation

> US National Institutes of Health, RePORTER application 9876929, Small Molecules Modulating CBX7 Protein as Potential Anticancer Agents (5R03CA238559-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9876929. Licensed CC0.

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