# Allosteric Modulators of Src-family Kinases for Acute Myeloid Leukemia

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $30,036

## Abstract

Abstract
The eight mammalian Src-family members are non-receptor protein-tyrosine kinases which are involved in nearly
all cell signaling pathways. Hck and Fgr are members of this family expressed almost exclusively in myeloid
hematopoietic cells and their progenitors. The overexpression of these kinases has been linked to the
development of, and a poorer prognosis in, acute myeloid leukemia (AML). AML is a common form of blood
cancer in adults, with nearly 20,000 new cases per year in the US. About one-third of AML cases have activating
mutations in the Flt3 receptor tyrosine kinase, including point mutations and internal tandem duplications. Current
treatments for this subset of AML patients include ATP-site kinase inhibitors, although acquired resistance
mutations commonly develop within one year of the start of treatment. Inhibitors for Hck and Fgr are also
emerging as a new approach to AML therapy. Our group recently identified small molecules that bind to the
regulatory domains of Hck (unique-SH3-SH2-linker) as opposed to the ATP-binding site of the kinase domain.
Binding data and docking models suggest that these compounds bind to a site that requires a specific 3D-
conformation of the SH3 and SH2 domains. They also decrease the viability of an AML cell line that
overexpresses active Hck and Fgr. Based on these results, we hypothesize that these compounds suppress
AML cell growth by interfering with downstream signaling via the SH3 and SH2 domains. In addition, the
compounds may allosterically influence the conformation of the active site to favor ATP-site inhibitor action. We
aim to expand upon these findings using in vitro kinase and binding assays to explore selectivity within the Src-
kinase family and possible synergy with ATP-site inhibitors. The anti-AML mechanism of action of the
compounds will be tested in AML cell line models by correlating their effects on kinase activity and downstream
substrate activation with growth suppression and apoptosis. Finally, we will determine the binding site for these
putative allosteric inhibitors within Hck by X-ray crystallography. These experiments will provide crucial insight
for the future development of these novel compounds as a treatment for AML, either as stand-alone therapy or
in combination with existing ATP-site inhibitors.
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## Key facts

- **NIH application ID:** 10314948
- **Project number:** 1F31CA265294-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ari Selzer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314948

## Citation

> US National Institutes of Health, RePORTER application 10314948, Allosteric Modulators of Src-family Kinases for Acute Myeloid Leukemia (1F31CA265294-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10314948. Licensed CC0.

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