# Developing a Selective PROTAC of Anaplastic Lymphoma Kinase for Treatment of ALK+ NSCLC

> **NIH NIH U54** · XAVIER UNIVERSITY OF LOUISIANA · 2024 · $514,185

## Abstract

Project Summary
The American Cancer Society estimates that 238,000 Americans will be diagnosed with lung
cancer in 2023 and over 127,000 Americans will die of lung cancer complications. Non-small cell
lung cancer (NSCLC) accounts for the vast majority (~82%) of all lung cancer diagnoses and can
be caused by a number of distinct mechanisms. One such mechanism is an inversion of part of
Chromosome 2p that leads to the fusion of the tyrosine kinase domain of the Anaplastic
Lymphoma Kinase (ALK) gene with coiled-coil domain of echinoderm microtubule-associated
protein-like 4 gene (EML4), leading to a soluble, dimerized, constitutively active tyrosine kinase.
While a series of competitive ALK inhibitors have been approved by the FDA in the last decade,
spontaneous suppressor mutations in the ALK active site limit their efficacy, with median duration
of response of 11 months. Rather than continue to develop ALK inhibitors, we have developed a
series of proteolysis-targeting chimeras (PROTACs) to induce the degradation of the EML4-ALK
protein. These heterobifunctional PROTACs are small molecules that contain an EML4-ALK
targeting motif, a flexible linker, and a ligand that recruits an E3 ubiquitin ligase. This complex
induces the ubiquitination and subsequent proteasome-mediated degradation of the target protein.
In cellular assays, we see that our early stage PROTACs induce degradation of transformed,
NSCLC-causing EML4-ALK fusions, as well as EML4-ALK with suppressor mutations that block
the efficacy of currently approved therapeutics. Importantly, we observe EML4-ALK degradation
for concentrations at or lower than those used for current inhibitors. In the initial stages of this
proposal, we will perform iterative synthesis and testing of additional PROTAC molecules to
increase both their selectivity and effectiveness in in vitro and cellular studies. Once we have
obtained the most promising candidates for further development, we will test them for a
comprehensive set of pharmaceutical criteria including desirable ADME and safety pharmacology
profile, pharmacodynamics, pharmacokinetics, in vivo efficacy, and oral bioavailability.
PROTACs that meet such criteria will then be tested in clinically relevant xenograft ALK-positive
NSCLC tumor models to evaluate in vivo efficacy and pharmacodynamics, as well as additional
ADME and PK studies. This work will develop a first-in class, orally active ALK degrader that can
be used for patients that have become resistant to first-line inhibitor treatment. In addition, ALK
degraders have the potential to be used as a first-line treatment as well, since they have already
shown efficacy in degrading non-resistant forms of EML4-ALK fusions.

## Key facts

- **NIH application ID:** 10932354
- **Project number:** 5U54MD007595-17
- **Recipient organization:** XAVIER UNIVERSITY OF LOUISIANA
- **Principal Investigator:** THOMAS M HUCKABA
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $514,185
- **Award type:** 5
- **Project period:** 2009-09-24 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932354

## Citation

> US National Institutes of Health, RePORTER application 10932354, Developing a Selective PROTAC of Anaplastic Lymphoma Kinase for Treatment of ALK+ NSCLC (5U54MD007595-17). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/10932354. Licensed CC0.

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