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Overcoming drug resistance with EAI-432, an allosteric EGFR inhibitor for non-small cell lung cancer

*November 2023*

Note: Allosteric inhibitors are an exciting new possibility to treat osimertinib resistance but are still in preclinical stage of development.

Researchers at Dana-Farber Cancer Institute have developed a promising new drug candidate, EAI-432, to treat non-small cell lung cancers (NSCLC)driven by mutations in the EGFR gene, particularly the L858R mutation which is present in about one-third of NSCLC patients.

EAI-432, an allosteric inhibitor with high selectivity for the L858R mutation and subsequent clinical resistance mutations, provides a potential new approach for NSCLC patients for whom there are currently no approved targeted therapies. Combination with the current frontline therapy may also lead to enhanced outcomes, delaying the emergence of resistance in that patient population.

Approved EGFR inhibitors bind to the active site of the EGFR target, known as the ATP binding pocket. Unlike other fourth-generation compounds in development, EAI-432, binds to a site separate from the active ATP pocket on EGFR, causing conformational changes and effectively inhibiting it.

Preclinical studies presented at the AACR-NCI-EORTC meeting in October show that EAI-432 can co-bind with other EGFR-targeted inhibitors, representing a potential strategy for improving patient outcomes. In the poster presentation, Dana-Farber scientists shared that EAI-432 co-binds with osimertinib, a third-generation EGFR inhibitor, which is the standard-of-care therapy for patients with EGFR mutations. EAI-432 has good oral pharmacokinetics, is brain-penetrant, and has demonstrated promising efficacy in mouse xenograft models.

“Since EAI-432 binds in a different pocket to other EGFR inhibitors, it should address many of the resistance mechanisms that emerge and represents a potential new therapy for patients who have become resistant to the standard of care,” says David Scott, Ph.D., director, Medicinal Chemistry Core at Dana-Farber. The compound may also be helpful in combination with current EGFR inhibitors like osimertinib as initial treatment in patients with the L858R mutation. Read more.