# Structural Studies of a T cell Specific Tyrosine Kinase

> **NIH NIH R01** · IOWA STATE UNIVERSITY · 2022 · $452,013

## Abstract

Project Summary
The TEC family kinases are expressed in cells of hematopoietic origin and play key roles
in immune cell signaling cascades during development and immune activation. Two TEC
kinases, ITK and BTK are the focus of this application and are both recognized as
important targets in efforts to treat immune related diseases. For example, the active site
BTK inhibitor, ibrutinib, is used to treat chronic lymphocytic leukemia but new approaches
are needed as drug resistance is foiling efforts to slow progression of disease. The current
renewal application takes a multifaceted approach to this problem. First we are
capitalizing on the mechanistic findings from the previous award period by carrying out
several orthogonal screens for small molecule discovery. The findings so far suggest we
have successfully identified small molecule reagents that bind to the TEC kinases and
modulate T- and B-cell signaling. The screening approaches are designed to uncover
allosteric modulators of kinase activity and in this way we aim to develop the means to
overcome ibrutinib resistance with combination therapies as well as generally define
alternative – outside of the active site - approaches to kinase inhibition. In additional
research objectives, we use our arsenal of biophysical tools (NMR spectroscopy,
hydrogen/deuterium exchange mass spectrometry, and x-ray crystallography) in addition
to biochemical and cellular assays to understand how mutations that drive drug resistence
or oncogenicity alter the structure, dynamics and function of the full-length ITK and BTK
kinases. The molecular level knowledge that will emerge from this work will provide a
better understanding of T cell and B cell signaling and the means to target specific
interactions or allosteric regulatory mechanisms for therapeutic uses.

## Key facts

- **NIH application ID:** 10459324
- **Project number:** 5R01AI043957-24
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** AMY H ANDREOTTI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $452,013
- **Award type:** 5
- **Project period:** 1999-01-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459324

## Citation

> US National Institutes of Health, RePORTER application 10459324, Structural Studies of a T cell Specific Tyrosine Kinase (5R01AI043957-24). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10459324. Licensed CC0.

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