# Defining the relationship between kinase inhibitor pharmacophores and pro-/anti-targets using in vivo models of colorectal cancer

> **NIH NIH K00** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $95,308

## Abstract

Project Summary
 Drug resistant cancers are an unfortunate global health problem that affects millions of
families [6]. Inhibitors targeting cancers caused by mutations in the kinase domain of receptor
tyrosine kinases often target the ATP binding site [7]. Although this method of treatment is
generally very effective, mutations at the “gate-keeper” position and residues farther away from
the drug binding site not only cause weakened binding affinity for the drug, but can also increase
kinase activity in the absence of drug. Addressing additional kinase activation is a major concern
as undruggable cancers can easily continue to spread.
 My dissertation research aims to understand and quantify the effects these mutations have
on kinase activation and thermodynamic stability using the kinase domain from the fibroblast
growth factor receptor (FGFRs) family as a model system. Recently, we elucidated an allosteric
network of residues in FGFR kinases spanning from the hinge region to the activation loop that
are associated with activation. Using NMR relaxation experiments to provide residue specific
information, I plan to quantify the effects of the gate-keeper mutant found in rhabdomysarcoma,
and a hinge mutant, recently found to severely weaken inhibitor binding, on kinase dynamics.
These dynamics will provide a clear picture of how these mutations hijack the kinase's allosteric
network to increase activity and explain how hinge mutations far from the drug-binding site can
confer resistance. Differential scanning calorimetry will also be employed to understand how drug
resistant mutations affect the stability of the kinase in the apo and drug-bound form. Findings from
this work will have major implications for future drug design to overcome these types of drug
resistance mutations.

## Key facts

- **NIH application ID:** 10086071
- **Project number:** 5K00CA212474-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** William M Marsiglia
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $95,308
- **Award type:** 5
- **Project period:** 2019-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086071

## Citation

> US National Institutes of Health, RePORTER application 10086071, Defining the relationship between kinase inhibitor pharmacophores and pro-/anti-targets using in vivo models of colorectal cancer (5K00CA212474-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10086071. Licensed CC0.

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