9rke
Crystal Structure of compound 1-mediated ternary complex of KRAS G12R GCP with pVHL:ElonginC:ElonginB
Structural highlights
FunctionELOB_HUMAN SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).[1] [2] The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.[3] [4] Publication Abstract from PubMedKirsten rat sarcoma viral oncogene homologue (KRAS) is a frequently mutated oncogene in multiple types of cancer and is a high priority target for oncology drug development. There are many different KRAS mutations, including mutations that favor the GTP-loaded hydrolysis-incompetent "active" state of KRAS, KRAS(on), that can lead to tumorigenesis. However, small molecule interventions thus far have predominantly targeted single mutations of "inactive" GDP-loaded KRAS, KRAS(off), such as KRAS(G12C). Here, we address this gap through the development of heterobifunctional VHL-based PROTACs capable of engaging and degrading KRAS(on), thus addressing a wider range of KRAS mutations. By studying ternary complex affinity, stability, and binding modes using SPR and X-ray cocrystal structures, we identified PROTACs that exhibit high positive cooperativity in forming ternary complexes with VHL and GCP-loaded KRAS as representative of KRAS(on) variants. Degrader activity profiling in relevant cancer cells supported the discovery of ACBI4, a PROTAC which forms a highly stable and cooperative ternary complex between VHL and GTP-bound KRAS and which potently degrades KRAS(G12R), leading to antiproliferative effect in KRAS mutant-driven cancer cells. ACBI4 provides a new chemical tool for studying the impact of degrading KRAS(on) mutants, which is not possible with current pan-KRAS inhibitors or degraders. Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles.,Vetma V, Puoti I, Karolak NK, Chakraborti S, Diers E, Girardi E, Khan S, Kidd G, Kropatsch KG, Mclennan R, O'Connor S, Samwer M, Trainor N, Whitworth C, Wijaya AJ, Wong JYF, Zollman D, Farnaby W, Popow J, Ciulli A, Ettmayer P, McAulay K J Am Chem Soc. 2025 Oct 30. doi: 10.1021/jacs.5c10354. PMID:41166656[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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