# Studies of mutant-selective allosteric inhibitors of EGFR for non-small cell lung cancer

> **NIH NIH F32** · DANA-FARBER CANCER INST · 2021 · $66,390

## Abstract

PROJECT ABSTRACT
Lung cancer is the most common and highest mortality type of cancer and is frequently the result of activating
mutations to the epidermal growth factor receptor (EGFR). Due to the emergence of resistance mutations in
patients treated with EGFR inhibitors, allosteric inhibitors targeting EGFR mutants have shown promise as the
next generation of therapeutics. With their distinct binding sites, canonical, ATP-competitive inhibitors can bind
simultaneously and cooperatively with allosteric inhibitors to synergistically kill cancer cells in vivo. Combination
of EGFR inhibitors with different mechanisms of action represents a new paradigm for targeting tumors that are
refractory to current monotherapies through the exploitation of cooperative binding principles.
The long-term goal of this project is to understand the mechanism of action of cooperative kinase inhibitor binding
to oncogenic and drug resistant variants of EGFR to aid in the development of novel combination therapies for
EGFR-driven lung cancers. Structural and pharmacological methods will be used to define cooperative binding
mechanisms and synergy of different combinations of ATP-competitive and allosteric inhibitors in the context of
clinically-relevant EGFR variants to understand the effects of these mutations on co-binding. Insights garnered
from these studies will be used to rationally design and synthesize complimentary pairs of inhibitors with
enhanced cooperativity. The resulting inhibitor combinations may be able to overcome common resistance
mutations or display enhanced selectivity for oncogenic variants of EGFR over wild-type.
The proposed project will take place at the Dana-Farber Cancer Institute (DFCI), a leading research center for
cancer research, and will benefit greatly from its strong translational therapeutics program. The proposed project
takes into account the trainee’s strengths in protein biochemistry and structural biology while providing training
in medicinal chemistry and cancer biology. Through DFCI’s affiliation with Harvard Medical School, the trainee
will take courses in cancer cell biology and synthetic chemistry, present at departmental seminars and
conferences, and mentor students. The sponsors of this project are experts in the fields of EGFR pharmacology
and kinase inhibitor chemistry and will allow the trainee to assist in writing relevant grant proposals to provide
training in technical writing and budgeting. The trainee will be the primary contact with regard to project
collaborations and will be in charge of initiating and coordinating manuscripts describing the results of this project.

## Key facts

- **NIH application ID:** 10189494
- **Project number:** 5F32CA247198-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Tyler Steven Beyett
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 5
- **Project period:** 2020-06-04 → 2023-06-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189494

## Citation

> US National Institutes of Health, RePORTER application 10189494, Studies of mutant-selective allosteric inhibitors of EGFR for non-small cell lung cancer (5F32CA247198-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189494. Licensed CC0.

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