# Small molecule inhibitors of LMPTP: an obesity drug target

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $500,608

## Abstract

ABSTRACT
The objective of this renewal grant proposal is to perform preclinical validation of an inhibitor of the low molecular
weight protein tyrosine phosphatase (LMPTP) as a therapeutic treatment for obesity-associated diabetes.
Diabetes caused by insulin resistance is a major cause of obesity-associated morbidity. The currently available
anti-diabetic treatments are often insufficient to maintain glycemic control in type 2 diabetes patients; thus there
is a major unmet medical need for agents that lower insulin resistance. Targeting tyrosine phosphatases that
inhibit insulin signaling by dephosphorylating the insulin receptor (IR) is considered a potential strategy for
treating type 2 diabetes by sensitizing the cellular response to insulin. The tyrosine phosphatase LMPTP inhibits
insulin signaling by dephosphorylation of the activation motif of the IR. In humans, genetic polymorphisms
encoding low LMPTP activity associate with lower glycemic levels. We discovered that LMPTP is a key promoter
of obesity-induced insulin resistance by inhibiting IR phosphorylation in the liver. Mice carrying global and liver-
specific LMPTP deletion gain comparable weight to control littermate mice when fed a high-fat diet, however
display substantially improved glucose tolerance and lower fasting insulin levels. During the previous grant
funding cycle, through a screening of the Molecular Libraries Probe Production Centers Network chemical library
followed by an extensive hit-to-lead optimization campaign, we exploited unique structural features of LMPTP to
generate a new class of inhibitors that is orally bioavailable, exclusively selective for LMPTP over other tyrosine
phosphatases, and lowers insulin resistance and restores glucose tolerance in obese diabetic mice. Our long-
term goal is to advance an LMPTP inhibitor to the clinic as a therapeutic option for patients with type 2 diabetes.
Thus here we apply for continued grant funding to collect preclinical efficacy and safety data and perform
chemical optimization in order to generate a candidate for investigational new drug-enabling studies. We will
accomplish this objective by pursuing 3 Specific Aims: 1) validation of the LMPTP inhibitor lead efficacy in human
hepatocytes and in mouse models of obesity-induced diabetes; 2) validation of the LMPTP inhibitor lead safety
in mice; 3) generation of an optimized LMPTP inhibitor lead through iterative cycles of structure-guided medicinal
chemistry.

## Key facts

- **NIH application ID:** 9982932
- **Project number:** 5R01DK106233-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Nunzio Bottini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $500,608
- **Award type:** 5
- **Project period:** 2015-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982932

## Citation

> US National Institutes of Health, RePORTER application 9982932, Small molecule inhibitors of LMPTP: an obesity drug target (5R01DK106233-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9982932. Licensed CC0.

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