# Discovery of small molecule inhibitors for protein N-terminal acetyltransferase D

> **NIH NIH R01** · PURDUE UNIVERSITY · 2022 · $559,725

## Abstract

Emerging evidence implies that protein acetyltransferases play a crucial role in diverse
biological processes and various human diseases including cancer. Protein N-terminal
acetyltransferase D (NatD), also known as Naa40, Nat4, or Patt1, is a unique member of protein
N-terminal acetyltransferases because it only acetylates histones H2A and H4 that share the
identical N-terminal sequence of SGRGK. NatD has been reported to play an important role in a
variety of processes including remodeling of chromatin structure, cell migration and invasion, and
apoptosis. The elevated level of NatD in human lung and colorectal cancer tissues correlates with
poor clinical outcomes. Moreover, loss of NatD suppresses human lung cancer cell invasion and
decreases the tumor growth in colorectal cancer xenograft mice models. Hence, we hypothesize
that NatD is a compelling target for the development of novel cancer therapeutics for lung and
colorectal cancers. However, there are no specific small molecule probes available for NatD to
decipher the functions of NatD acetyltransferase activity in cancer. To fill this gap, our long-term
goal is to discover novel, potent, and selective small molecule NatD inhibitors. For this application,
we will employ a series of facile and reproducible high-throughput screening (HTS) assays with
orthogonal readouts to screen 400,000 diverse compounds from selected chemical libraries at
the Chemical Genomics Facility at Purdue Institute for Drug Discovery. Then we will characterize
active compounds in structural, mechanistic, selectivity, and cell-based studies. Upon completion
of this project, we expect to identify potent and selective first-in-class NatD small molecule
inhibitors as chemical probes for NatD function in cells. The knowledge gained from this project
would expedite the development of NatD modulators and our understanding of NatD-regulated
pathways in cancer patients.

## Key facts

- **NIH application ID:** 10366567
- **Project number:** 1R01CA258887-01A1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Rong Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $559,725
- **Award type:** 1
- **Project period:** 2021-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366567

## Citation

> US National Institutes of Health, RePORTER application 10366567, Discovery of small molecule inhibitors for protein N-terminal acetyltransferase D (1R01CA258887-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366567. Licensed CC0.

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