# RP5: Chemical proteomic discovery of small-molecule probes for autophagy proteins

> **NIH NIH U19** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $1,456,671

## Abstract

PROJECT SUMMARY – RP5
Small molecules that enhance autophagy have the potential to serve as therapeutics against a phylogenetically
diverse and broad range of pathogens. Nonetheless, most of the proteins that participate in, or regulate,
autophagy lack chemical probes and some may even be viewed as undruggable. To accelerate the discovery
of chemical probes, and ultimately drugs that promote anti-infective autophagy, new platforms are needed that
can broadly and efficiently evaluate small molecule interactions for autophagy-related proteins from diverse
structural and functional classes. Our laboratory has recently introduced the first chemical proteomic
platforms to globally assess the druggability of proteins directly in native biological systems. These
quantitative mass spectrometry-activity-based protein profiling (MS-ABPP) platforms can be applied to any cell
type or state and have identified small-molecule hit ligands for many hundreds of proteins across a wide range
of classes, including those previously considered undruggable (e.g., adaptors, transcription factors). Mining our
current MS-ABPP data sets of the human proteome, which contain 30,000+ sites on 10,000+ proteins, has
uncovered evidence of druggability for several proteins involved in degradative autophagy and/or ATG gene-
dependent immunity. In RP5, we will use our MS-ABPP platforms in close collaboration with RP1-4 to discover
and optimize small-molecule probes that enhance autophagy-mediated defense against infectious diseases.
We will pursue the following Specific Aims: 1) the chemical proteomic identification of protein targets of
autophagy-stimulating small molecules; 2) the chemical proteomic discovery of hit ligands for prioritized
autophagy proteins; 3) the chemical proteomic discovery of novel, druggable proteins that regulate autophagy;
and 4) the optimization of chemical probes for prioritized autophagy proteins. RP5 should furnish potent and
selective chemical probes for several prioritized autophagy proteins, and these probes will be provided to RP1-
4 for biological studies. The chemical probes developed in RP5 should also serve as much needed tools for
the greater autophagy and infectious disease communities, as well as valuable starting points for the
development of broad-spectrum anti-infective therapies.

## Key facts

- **NIH application ID:** 9893815
- **Project number:** 5U19AI142784-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** BENJAMIN F CRAVATT
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,456,671
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893815

## Citation

> US National Institutes of Health, RePORTER application 9893815, RP5: Chemical proteomic discovery of small-molecule probes for autophagy proteins (5U19AI142784-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9893815. Licensed CC0.

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