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STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique
Raymond A Pagliarini1, Jack A Henderson1, Benjamin C Milgram1
1Scorpion Therapeutics, Boston, Massachusetts.
Purpose:
Commonly occurring oncogenic mutations in EGFR render non-small cell lung cancers sensitive to approved EGFR-targeted drugs. EGFR in-frame exon 20 insertion (ex20ins) mutants are, however, less sensitive to such drugs. The efficacy of existing medicines may in part be limited by their selectivity for ex20ins mutations relative to wild-type EGFR, which is important for epithelial tissue homeostasis.
Experimental Design:
We solved high-resolution crystal structures of clinically frequent ex20ins mutants to better understand how to achieve mutant-selective inhibition. Analyses of these structures demonstrate targetable ex20ins-mutant-biased dynamic protein states. To exploit these findings, we designed STX-721, an irreversible EGFR/ERBB2 ex20ins-mutant-selective inhibitor, and characterized its activity relative to clinical phase benchmarks across multiple preclinical assays.
Results:
Structural analyses predict that STX-721 takes advantage of ex20ins-mutant-selective dynamic states. In carefully benchmarked biochemical, biophysical, and cellular assays, STX-721 demonstrated superior ex20ins-mutant selectivity relative to other tested benchmark clinical phase compounds and achieved ex20ins-mutant-selective tumor regression in vivo.
Conclusions:
These data highlight that STX-721 shows a high level of mutant EGFR selectivity across human preclinical cancer models and may provide an improved clinical efficacy versus adverse event profile relative to existing drugs.
Insights
A new drug, STX-721, shows high selectivity for EGFR exon 20 insertion mutations in non-small cell lung cancer. This targeted approach may improve treatment efficacy and reduce side effects compared to current therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epidermal growth factor receptor (EGFR) mutations drive non-small cell lung cancer (NSCLC).
- While some EGFR mutations sensitize tumors to targeted drugs, EGFR exon 20 insertions (ex20ins) confer resistance.
- Existing EGFR inhibitors show limited selectivity, impacting efficacy and causing side effects due to wild-type EGFR inhibition.
Purpose of the Study:
- To understand the structural basis of EGFR ex20ins mutants.
- To design novel inhibitors with enhanced selectivity for EGFR ex20ins mutants over wild-type EGFR.
- To develop STX-721, a potent and selective inhibitor for EGFR ex20ins NSCLC.
Main Methods:
- High-resolution crystal structure determination of EGFR ex20ins mutants.
- Design and synthesis of STX-721, an irreversible EGFR/ERBB2 inhibitor.
- Preclinical evaluation of STX-721 in biochemical, biophysical, cellular, and in vivo assays.
Main Results:
- Structural analysis revealed targetable mutant-biased dynamic protein states in ex20ins mutants.
- STX-721 demonstrated superior selectivity for ex20ins mutants compared to benchmark inhibitors.
- STX-721 achieved selective tumor regression in preclinical models harboring EGFR ex20ins mutations.
Conclusions:
- STX-721 exhibits high mutant EGFR selectivity in preclinical cancer models.
- This selectivity suggests potential for improved clinical efficacy and a better safety profile than existing treatments.
- STX-721 represents a promising therapeutic strategy for NSCLC patients with EGFR ex20ins mutations.
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