BI-0474, an irreversible covalent and selective KRAS G12C inhibitor, now available on opnMe
21 May 2024
The Kirsten rat sarcoma viral oncogene homologue (KRAS) protein is a small membrane-bound GTPase (GTP hydrolase), acting as a key node in intracellular signaling pathways that are involved in cell growth and survival. Mutations in the KRAS protein are the most common oncogenic driver mutations found in human cancers. The glycine-to-cysteine mutation at position 12 (G12C) of the KRAS protein interferes with the guanosine triphosphate (GTP) hydrolysis, thus keeping KRAS primarily in the active, GTP-bound state. This increased activity of the KRASG12C protein drives oncogenic signaling through multiple downstream pathways that directly promote tumor cell survival, proliferation and metastasis.
BI-0474 is an irreversible covalent KRASG12C inhibitor, developed using an NMR-based fragment screening approach pioneered at Vanderbilt University, whereby small molecules that bind reversibly to the KRAS switch II pocket were identified and optimized using structure-based design, and then a covalent “warhead” was attached. To enable further research on the KRASG12C mutation, you can now order BI-0474 as well as its negative control BI-0473 on opnMe.com. Both molecules are available free of charge and furthermore, you retain full ownership and control of your results, which we encourage you to publish.
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About BI-0474:
BI-0474 is a highly potent KRASG12C inhibitor showing a high second order rate (kinact/KI) and low KI in MS experiments detecting covalent protein modification of KRASG12C. It also shows in vivo biomarker modulation and in vivo efficacy in KRASG12C mutated xenograft models after intraperitoneal administration and therefore can be used as an in vitro or in vivo tool compound. The negative control BI-0473 is a diastereomer of BI-0474 showing a 200-fold lower biochemical activity compared to BI-0474.
About opnMe:
opnMe.com, the open innovation portal of Boehringer Ingelheim, fosters science and collaboration initiatives in areas of high unmet medical need. With “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 molecules, with the chance to get your research proposal funded. With our “opn2EXPERTS” and “techMATCH” programs, we enlist scientific advice on key scientific issues to fuel further drug discovery and deliver novel solutions that benefit unmet patient needs. Our newly launched “opn2TALENTS” postdoc grants awards opportunities for high-level talents to pitch their scientific ideas and approaches for a well-defined research question, to conduct their research at one of our discovery research sites in Germany, Austria, or the US.