Now on opnMe: BI-4732, a potent and brain-penetrant inhibitor against EGFR-activating mutations and on-target resistance mutations

18 November 2024

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that is activated when it binds to ligands from the EGF family. This induces receptor dimerization, tyrosine autophosphorylation, and leads to cell proliferation. It is widely expressed across multiple human tissues, including skin, brain, colon, liver, and lung, with highest expressions observed in the placenta. EGFR has also been implicated as a component of the cytokine storm which contributes to the severe form SARS-CoV-2 infections. Its role in human disease and in particular cancer has been well documented. Often it is associated with specific mutations that are prognostic and sometimes also causative to treatment failure. The most common activating mutations are deletions in exon 19 and a point mutation called L858R in exon 21.

EGFR inhibitors have been able to show clinical efficacy and have been able to obtain regulatory approval for various indications. However, there is a marked difference between those that bind extracellularly vs intracellularly. EGFR-tyrosine kinase inhibitors (TKI’s) belong to the latter group and interestingly their activity has been shown to be dependent on EGFR-activating mutations. However, for the first-and second-generation TKIs, cellular escape mechanisms eventually evolve that can be correlated to specific mutations such as the T790M mutation in exon 20. To overcome this, third-generation EGFR-TKIs such as osimertinib were developed, but also here, resistance had emerged due to the C797S mutation and other.

Now, we make a novel fourth-generation EGFR-TKI available on opnMe: BI-4732 is potent inhibitor against EGFR-activating mutations and on-target resistance mutations, with efficient activity in the central nervous system¹. It displays remarkable antitumor efficacy as a single agent in various patient derived models with EGFR C797S-mediated osimertinib resistance.

BI-4732 can be used to investigate the effects of different mutations on the EGFR signaling pathway. Interested researchers will receive the molecule free of charge and have full ownership of their results. We encourage you to publish your findings as part of our commitment to open science.

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About BI-4732:

As a fourth generation EGFR targeting agent, BI-4732 is a novel reversible and ATP-compatible tyrosine kinase inhibitor. It inhibits the kinase activity of EGFR L858R, T790M, and C797S with IC₅₀ values of 1 nM while sparing wildtype EGFR. The compound is suitable for in vitro cellular experiments as well as in vivo studies. It complements the EGFR inhibitor BI-8128 that we have shared previously via opnMe.

About opnMe:

opnMe.com, the open innovation portal of Boehringer Ingelheim, fosters science and collaboration initiatives in areas of high unmet medical need. As part of our first pillar, the “Molecules to Order”, we share well-characterized tool compounds free of charge with no IP strings attached. These are complemented by “Molecules for Collaboration” where we offer access to unprecedented, often unpublished molecules, together with an attractive funding package. Interested scientists are invited to submit testable research hypotheses with these assets in novel diseases or combinations. With our “opn2EXPERTS” and “techMATCH” programs, we enlist scientific advice on key biologic issues to fuel further drug discovery and deliver novel solutions that benefit unmet patient needs. Our opn2TALENTS PostDoc grants, provide an opportunity for high-caliber talents to pitch their scientific approaches for well-defined research questions to conduct their research at one of our discovery research sites.