# Development of a first-in-class mEGFR dimerization inhibitor

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $419,222

## Abstract

Background: Lung cancers are often driven by mutant epidermal growth factor receptor (mtEGFR). While
EGFR tyrosine kinase activity inhibitors (TKI) have shown effectiveness, within 9-13 months all patients
develop resistance including to 3rd generation TKI - Osimertinib. These patients do not have any approved
therapy options, therefore, there is an urgent need to develop a novel agent that functions independently of
kinase function. DGD1202, a first-in-class, novel, orally bioavailable, small molecule that inhibits EGFR
dimerization, induces degradation of EGFR and selectively kills TKI resistant NSCLC tumors.
Objective: We and others have shown that the degradation of mutant EGFR protein has a profound effect on
cancer cell survival. Thus, we hypothesized that a drug which induces degradation of mtEGFR independent of
the ATP binding domain will result in selective activity. Our objective is to evaluate the therapeutic potential of
DGD1202 in a panel of lung cancer cells lines, xenografts, and PDXs derived from lung cancer patients
containing mtEGFR who have undergone treatment with a TKI.
Specific Aims: We propose to evaluate the specificity and potency of DGD1202 against TKI-resistant lung
cancer cells and xenografts. Aim 1 is to determine the in vitro efficacy of DGD1202 against a panel of EGFR
driven, including osimertinib-resistant, cancer cell lines relative to normal cells. Aim 2 is to conduct in vivo
pharmacokinetic (PK) and pharmacodynamic (PD) analyses to assess drug exposure and determine the effect
on the target. Aim 3 is to determine the overall therapeutic efficacy and long-term safety of DGD1202 in vivo.
We hypothesize that treatment with DGD1202 will induce EGFR degradation preferentially in tumor cells driven
by mtEGFR and that EGFR degradation will correlate with the overall response.
Study Design: We will screen DGD1202 alongside osimertinib in a series of lung cancer lines. The resulting
response will be then correlated with effect on EGFR degradation. We also propose to determine in vivo PK
and PD studies both with a single and with fractionated dosing to determine the optimum bioavailability. Using
the optimized dose and schedule, we will assess effects on EGFR protein against a panel mtEGFR-driven and
osimertinib resistant lung cancer xenograft and PDX models. The long-term safety will be assessed in immune
competent mice. Standard statistical models will be used to compare the response to treatment and how it
correlates with effects on EGFR.
Impact: We anticipate that our approach will open a new way to target EGFR and, more broadly, to develop
therapeutics to selectively target mutated proteins to degradation. The knowledge gained from in vivo tumor
models will provide a rationale for the use of this class of molecules in future clinical studies.

## Key facts

- **NIH application ID:** 9944762
- **Project number:** 1R01CA248310-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** THEODORE S LAWRENCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,222
- **Award type:** 1
- **Project period:** 2020-04-03 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944762

## Citation

> US National Institutes of Health, RePORTER application 9944762, Development of a first-in-class mEGFR dimerization inhibitor (1R01CA248310-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944762. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*