# Chemoproteomic Identification and Therapeutic Validation of Proteins of Metabolic Significance

> **NIH NIH RC2** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $1,640,587

## Abstract

Abstract
There is a need to develop diabetes drugs with a mechanism of action distinct from that of established agents.
Defects in adipocyte function drive the onset of systemic insulin resistance and obesity-linked diabetes. The
ability of hypertrophied adipocytes to dispose of glucose and lipids and secrete insulin-sensitizing adipokines is
severely compromised and this contributes to hyperglycemia, hyperlipidemia, insulin resistance, inflammation,
and lipid deposition in tissues such as liver where it dampens insulin action. Agents that can revert these
defects and restore natural lipid partitioning amongst tissues are useful insulin sensitizers in humans. The
critical challenge that this project addresses is the identification and therapeutic validation of new molecular
pathways that can be pharmacologically modulated to revert adipocyte defects and restore insulin signaling in
liver and other tissues.
Our multidisciplinary team will achieve this goal by combining cutting-edge phenotypic screening and
chemoproteomic technologies, with deep expertise in adipose tissue and liver biology and lipid metabolism.
We have developed innovative strategies that integrate phenotypic screening with chemoproteomics to
streamline the identification of protein targets of bioactive small molecules, which we initially applied to
enzymes of the serine hydrolase family, but have more recently extended for proteome-wide investigations.
We propose to complement our initial serine hydrolase-focused approach with our new powerful platforms for
integrated phenotypic screening and chemical biology to enable the rapid, systematic, and proteome-wide
discovery of metabolism targets. By screening unique libraries of small-molecules for desirable phenotypes in
adipocytes and hepatocytes in an unbiased manner, we will identify in tandem physiologically relevant proteins
and chemical tools to perturb the function of these proteins to expedite their functional annotation and
therapeutic validation in diabetes and NASH. In the process, we will create first-in-class chemical probes and
genetic models to study key metabolic pathways that will be distributed to the larger research community.
Our cutting-edge chemical biology platforms radically expand the portion of the proteome that can be targeted
with small molecules. Application of these tools to the central problem that drives diabetes endows this project
with unparalleled potential to discover new targets to treat diabetes and associated conditions.

## Key facts

- **NIH application ID:** 9986787
- **Project number:** 5RC2DK114785-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** BENJAMIN F CRAVATT
- **Activity code:** RC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,640,587
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986787

## Citation

> US National Institutes of Health, RePORTER application 9986787, Chemoproteomic Identification and Therapeutic Validation of Proteins of Metabolic Significance (5RC2DK114785-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986787. Licensed CC0.

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