# Receptor PTPs, Cell Contact and Signal Transduction

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2020 · $480,000

## Abstract

PROJECT SUMMARY/ ABSTRACT
Approximately 30% of the world’s population is now classified as obese or overweight; this high incidence is
associated with increased risk of cardiovascular disease, cancer and diabetes, and reflects a worldwide
healthcare crisis. At this time new therapies are needed urgently. The broad, long-term objectives of this project
are to validate a new paradigm for drug discovery efforts in this area. A major emphasis in drug discovery today
involves targeting changes in signal transduction pathways that are critical drivers of a disease state, so as to
address specifically the etiology of that disease. Insulin and leptin trigger tyrosine phosphorylation-dependent
signaling pathways that control appetite and feeding, energy expenditure and glucose homeostasis. In fact,
diabetes and obesity are diseases of insulin- and leptin-resistance, respectively. This drew attention to those
members of the family of protein tyrosine phosphatases (PTPs) that would normally attenuate these signaling
pathways as potential therapeutic targets. Pharmacological inhibition of these PTPs would be expected to
promote signaling and help to overcome the resistant state. Major programs in industry focused on developing
small molecule PTP inhibitors, but they have been frustrated by technical challenges arising from the chemical
properties of the PTP active site. As a result, industry classifies PTPs as potentially “non-druggable” and they
remain a largely untapped resource for drug development. Nevertheless, the extensive biological data validating
phosphatases, such as PTP1B, as therapeutic targets, emphasizes the importance of discovering new
approaches to inhibitor development that circumvent the problems encountered with active site-directed
inhibitors. Therein lies the opportunity for academia, with its freedom to think without boundaries and to challenge
existing paradigms. It is perhaps only in academia that new and innovative approaches, such as described in
this proposal, can be taken to develop strategies that exploit areas and targets currently overlooked by industry,
thereby benefiting patients through discovery of new therapies. This proposal, which builds on the foundation of
progress during previous funding periods, addresses this problem from a unique and innovative perspective.
The emphasis remains on defining and harnessing a novel mechanism for physiological regulation of PTP
function by reversible oxidation in response to stimuli, such as insulin and leptin. In the previous funding period,
we characterized scFv antibodies that recognize and sequester the oxidized, inactive form of PTP1B, promoting
enhanced and sustained insulin signaling. In addition, we provided proof of concept for small molecule inhibitors
that mimic the effects of these antibodies. In this competing renewal, addressing the following Specific Aims will
develop further this unique approach to drug development for the treatment of diabetes and obesity: 1: To defi...

## Key facts

- **NIH application ID:** 9972089
- **Project number:** 9R01DK124907-21
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** NICHOLAS K TONKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,000
- **Award type:** 9
- **Project period:** 1997-05-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972089

## Citation

> US National Institutes of Health, RePORTER application 9972089, Receptor PTPs, Cell Contact and Signal Transduction (9R01DK124907-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972089. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*