# Core A: Medicinal Chemistry

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2021 · $290,534

## Abstract

Activating mutations and genetic alterations in protein kinase encoding genes, such as EGFR,
HER2, KRAS, BRAF, ALK and ROS1, have been demonstrated to be oncogenic “drivers” in
human lung cancer. Protein kinases harboring such activating alterations have proven to be
amenable to inhibition by small molecule inhibitors of enzymatic activity. During the previous
funding period this Core was highly productive in establishing new inhibitors and helped
advance concepts for developing mutant-selective EGFR inhibitors and first-in-class inhibitors of
DDR1 and DDR2. In addition, we developed the first allosteric inhibitors of EGFR which can
overcome resistance mutations that emerge in the ATP-binding site. Unfortunately, despite
dramatic clinical response to targeted agents, resistance inevitably emerges. The goal of the
Chemistry Core (Core A) is to address this challenge by advancing fundamentally new
pharmacological approaches for these targets, including the development of novel allosteric
inhibitors. In particular, we will exploit a recently described approach involving the development
of bi-valent small molecules that induce ubiquitination and subsequent proteosomal degradation
of targets of interest. We will use ligands related to thalidomide, which can recruit the E3 ligase,
cereblon, that we call ‘selective degraders’ (they are also sometimes called PROTACs or
degronimids). The Core will develop, refine and provide access to inhibitors and clinical stage
compounds required by the Program investigators. The Core will accomplish this goal by
collaborating with all three Research Projects and the other Resource Cores to identify and
optimize selective degraders for mutant forms of EGFR (Project 1; Leader, Jänne), c-RAF &
Mek1/2 (Project 2; Leader, Hahn and co-Leader, Barbie), and transcriptional cyclin dependent
kinases (CDKs; Project 3; Leader, Hammerman and co-Leader, Meyerson) using a focused
medicinal chemistry approach. Through collaborations with the three Projects, the Structure
Core (Director, Eck), and the Animal Core (Director, Wong), the Chemistry Core will perform
medicinal chemistry to develop and optimize inhibitors—to be used alone or as “selective
degraders”—that exhibit the potency, selectivity, and pharmacological properties sufficient to
enable their use in the proposed cellular and in vivo studies.

## Key facts

- **NIH application ID:** 10231102
- **Project number:** 5P01CA154303-10
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** NATHANAEL Schiander GRAY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $290,534
- **Award type:** 5
- **Project period:** 2012-05-11 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231102

## Citation

> US National Institutes of Health, RePORTER application 10231102, Core A: Medicinal Chemistry (5P01CA154303-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10231102. Licensed CC0.

---

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