ACBI3, a first-in class VHL PROTAC selectively targeting KRAS, now available on opnMe

30 September 2024

The Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most mutated oncogene in human cancers. Through opnMe, we now offer ACBI3, a first-in-class proteolysis targeting chimera (PROTAC), which arises from a successful collaboration with the University of Dundee (Centre for Targeted Protein Degradation, School of Life Sciences), and has been recently published in Science¹. This molecule selectively targets KRAS with high potency, while sparing its paralogues H- and NRAS. ACBI3 potently degrades 13 out of 17 of the most prevalent oncogenic KRAS variants, leading to more profound and sustained pathway modulation. ACBI3 is the first example of a single agent capable of targeting simultaneously a major share of highly prevalent KRAS-activating variants. Consequently, ACBI3 inhibits the proliferation of most cancer cell lines driven by KRAS mutations, while sparing those without genetic KRAS aberrations. Adequately formulated, ACBI3 achieves degradation of oncogenic KRAS protein levels in vivo. This leads to a potent and long-lasting reduction of KRAS signaling, resulting in tumor regression in specific models. This more broadly suggests fundamental advantages for targeting a spectrum of chemically heterogenous disease-relevant protein variants by targeted protein degradation.

To facilitate further research on KRAS, you can now order ACBI3 as well as its negative control cis-ACBI3 on opnMe.com. Both molecules are shipped free of charge and moreover, you retain full ownership and control of your results, which we encourage you to publish.

Order today to start your research

No registration required

Subscribe to our newsletter to stay updated as we add new molecules to opnMe.com.

About ABCI3:

ACBI3 is a highly potent KRAS-targeting VHL PROTAC, developed in collaboration with the University of Dundee. It was discovered via a structure-based design approach guided by optimization of VHL:PROTAC:KRAS ternary complex stability and durability. It degrades KRAS via ubiquitin ligase recruitment with a more than 10-fold higher potency compared to target inhibition and results in prolonged suppression of MAPK signaling. ACBI3 shows antiproliferative activity in a cell line panel on KRAS mutant but not KRAS^WT cell lines and in vivo efficacy in reducing KRAS signaling. The VHL binding deficient stereoisomer cis-ACBI3 displays deficient binding to VHL, and hence can be used as a negative control for KRAS degradation. Note, however, that cis-ACBI3 still binds KRAS and acts as a non-covalent KRAS inhibitor.

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.