29 June 2026
Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated oncogene in human cancer and has long been considered a particularly challenging target for direct pharmacological intervention. To further support the scientific community in studying KRAS‑driven biology, Boehringer Ingelheim is making ACBI4 available through opnMe.
ACBI4 is a first‑in‑class, VHL‑recruiting proteolysis‑targeting chimera (PROTAC) that selectively degrades activated, GTP‑loaded KRAS(on) oncogenic variants in vitro1. Designed in a successful collaboration with the University of Dundee (Centre for Targeted Protein Degradation, School of Life Sciences) as a highly cooperative degrader, ACBI4 stabilizes productive ternary complexes between KRAS and the VHL E3 ligase, resulting in rapid and profound degradation of multiple oncogenic KRAS alleles, including difficult‑to‑target variants such as KRAS G12R.
By enabling selective engagement of the active KRAS state, ACBI4 provides a valuable tool to interrogate oncogenic KRAS signaling in ways not accessible with conventional inhibitors or existing pan‑KRAS degraders. ACBI4 induces antiproliferative effects in KRAS‑mutant cancer cell models while sparing KRAS wild‑type systems, supporting its use as a mechanistic in vitro research tool.
To facilitate robust experimental design, ACBI4 is complemented by its matched negative control, cis‑ACBI3, which retains KRAS binding but is deficient in VHL recruitment.
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About ACBI4:
ACBI4 is a highly potent VHL-recruiting PROTAC designed to selectively degrade activated, GTP-loaded oncogenic KRAS variants in vitro. The molecule was developed through structure-guided optimization of the KRAS:PROTAC:VHL ternary complex and enables state-selective targeting of KRAS signaling.
ACBI4 induces efficient degradation of multiple oncogenic KRAS variants, resulting in suppression of downstream signaling and antiproliferative effects in KRAS-driven cancer cell models. Due to limited solubility and lack of oral bioavailability, ACBI4 is intended as an in vitro tool. The negative control, cis-ACBI3, contains the same KRAS-binding moiety but is deficient in VHL recruitment and can be used to validate degradation-dependent effects.
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 “Molecules to Order” pillar, we share well-characterized tool compounds free of charge with no IP strings attached. With “opn2EXPERTS”, 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.
Reference:
- Vetma V., Puoti I., Karolak N. K., Chakraborti S., Diers E., Girardi E., Khan S., Kidd G., Kropatsch K. G., Mclennan R., O'Connor S., Samwer M., Trainor N., Whitworth C., Wijaya A. J., Wong J. Y. F., Zollman D., Farnaby W., Popow J., Ciulli A., Ettmayer P., McAulay K. Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles J Am Chem Soc. 2025, 147(45):41367-41378. DOI: 10.1021/jacs.5c10354, PubMed.