# Targeting ALK through Degradation and Allosteric Inhibitors

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $199,385

## Abstract

Project Summary
 Chromosomal rearrangements that generate fusion proteins of echinoderm microtubule-associated
protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK), known as EML4-ALK fusions, occur in 3-5% of
non-small cell lung cancer (NSCLC) cases. ALK is a validated therapeutic target for ALK rearranged NSCLC
patients with four ALK tyrosine kinase inhibitors (TKIs), crizotinib, alectinib, ceritinib and brigatinib, currently
approved by the food and drug administration (FDA) for the treatment of ALK rearranged lung cancers. All
currently approved ALK inhibitors, as well as those in clinical development, are ATP competitive kinase
inhibitors, which carry resistance liabilities. Several mechanisms of resistance to ALK inhibitors have already
been described and include both secondary mutations as well as activation of bypass signaling. Therefore, the
development of non-TKI based strategies for treatment of ALK rearranged cancers is urgently needed as a
complementary therapeutic approach. Here, we propose to explore a fundamentally new approach to
abrogating ALK function based on the use of small molecules that can selectively promote its degradation. In
particular, we will exploit a recently described approach involving the development of bivalent small molecules
called `selective degraders' (also known as PROTACs or degronimids) that induce ubiquitination and
subsequent proteosomal degradation of targets of interest. We will build our selective degraders using a dual
warhead strategy, with ligands that recruit E3 ligases, such as cereblon (CRBN) or Von Hippel-Lindau (VHL),
on one end and ALK binders on the other. Our multidisciplinary research team with expertise in medicinal
chemistry and drug development (Gray, Co-PI), and cancer biology and lung cancer translational research
(Jänne, Co-PI), has successfully discovered the first small molecule ALK degraders (shown in preliminary
data). The goal of this proposal is to develop optimized small molecule degraders of ALK (Aim 1), evaluate
their potential to overcome or prevent known mechanisms of resistance (Aim 2), and establish the efficacy of
optimized degraders in preclinical murine models (Aim 3). Successful completion of these aims will
demonstrate that a new class of compounds may be used to therapeutically target ALK-positive NSCLC, and
will provide well-validated compounds that may eventually be translated to clinical trials.

## Key facts

- **NIH application ID:** 10062479
- **Project number:** 5R01CA136851-12
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** NATHANAEL Schiander GRAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $199,385
- **Award type:** 5
- **Project period:** 2009-05-15 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062479

## Citation

> US National Institutes of Health, RePORTER application 10062479, Targeting ALK through Degradation and Allosteric Inhibitors (5R01CA136851-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10062479. Licensed CC0.

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