# Discovery and optimization of novel mutant-selective allosteric inhibitors of EGFR T790M

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $490,549

## Abstract

Abstract:
 Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are a
common cause of lung adenocarcinoma. Despite marked advances in targeted therapies for EGFR-mutant lung
cancer, treatment-acquired resistance remains a major problem.
 Understanding and overcoming acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) and to
other targeted therapies is a central problem in cancer medicine. Our long term goal is to develop more effective
and better tolerated therapies for EGFR mutant lung cancer that yield durable responses. We reason that
simultaneous treatment with multiple agents targeting mutant EGFR may prevent emergence of resistance
mutations, leading to more durable responses. However, suitable compounds with alternative mechanisms of
action have not previously been available. Like the vast majority of TKIs, all current EGFR TKIs target the ATP-
site of the kinase. Our multidisciplinary research team has deep expertise in EGFR-mutant lung cancer and a
record of successful inhibitor discovery. In the initial grant period, we developed highly potent allosteric inhibitors
based on a phenylglycine scaffold that are effective as single agents against L858R/T790M and
L858R/T790M/C797S EGFR variants in vitro and in mouse models of human non-small cell lung cancer. The
distinct mechanism of action and binding site of these allosteric inhibitors, together with their lack of potency on
WT EGFR and other protein kinases, makes them especially attractive as candidates for combination therapy.
 In this renewal, we will discover whether compounds that target the ATP and allosteric sites can indeed
synergize to deliver unprecedented efficacy, tolerability and durability of responses. We pursue this goal through
the following specific aims: Aim 1, We will develop a second chemical series of highly potent, mutant-selective
allosteric EGFR inhibitors based on a benzodiazepinone scaffold. Aim 2, We will design and optimize
complementary pairs of inhibitors that simultaneously bind the adjacent ATP and allosteric sites of mutant EGFR
with a high degree of positive cooperativity. To our knowledge, highly cooperative, multi-site inhibition has not
been previously explored in the context of therapeutic development. Aim 3, We will perform pre-clinical validation
of allosteric EGFR inhibitors and complementary ATP-site/allosteric pairs, including testing their in vivo efficacy
in xenograft models of EGFR mutant lung cancer and assessing the potential for resistance to arise in the context
of dual targeting. Successful execution of these aims will provide proof of concept for a new therapeutic approach
in EGFR mutant lung cancer.

## Key facts

- **NIH application ID:** 10121719
- **Project number:** 2R01CA201049-06
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** MICHAEL J ECK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $490,549
- **Award type:** 2
- **Project period:** 2015-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121719

## Citation

> US National Institutes of Health, RePORTER application 10121719, Discovery and optimization of novel mutant-selective allosteric inhibitors of EGFR T790M (2R01CA201049-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10121719. Licensed CC0.

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