# Discovery of Selective Inhibitors for Histone Methyltransferases

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $330,525

## Abstract

Discovery of Selective Inhibitors for Histone Methyltransferases 
 
 Histone methyltransferases (HMTs), which catalyze methylation of lysine or arginine residues of
histones and non-histone proteins, have been increasingly recognized as major players in regulating gene
expression and chromatin state. Growing evidence suggests that HMTs play crucial roles in the development
of many human diseases. Thus, HMTs have been increasingly pursued as potential therapeutic targets.
However, very few potent, selective and cell-active inhibitors of HMTs have been developed. In this project, we
propose to discover high quality inhibitors of HMTs by pursuing three complementary approaches: (1)
targeting a novel allosteric binding site; (2) targeting the substrate binding groove; and (3) targeting the
cofactor binding site. We have selected PRMT3 (a type I protein arginine methyltransferase), SETD8 (a
histone H4 lysine 20 monomethylase), and EZH2 and EZH1 (two closely related histone H3 lysine 27
methyltransferases) as representative HMT targets for these three approaches. We have generated
extensive and promising preliminary results for each of the three approaches, suggesting that our proposal is
feasible. We expect that successful completion of this project will: (1) produce a set of well-characterized
inhibitors as useful tools for the research community to investigate the roles of PRMT3, SETD8 and EZH2/1 in
health and disease; and (2) provide strong evidence that potent, selective and cell-active inhibitors of HMTs
can be generated by targeting an allosteric binding site, the substrate binding groove and cofactor binding site.

## Key facts

- **NIH application ID:** 9878874
- **Project number:** 5R01GM122749-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jian Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $330,525
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878874

## Citation

> US National Institutes of Health, RePORTER application 9878874, Discovery of Selective Inhibitors for Histone Methyltransferases (5R01GM122749-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878874. Licensed CC0.

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