8QVU

Crystal Structure of ligand ACBI3 in complex with KRAS G12D C118S GDP and pVHL:ElonginC:ElonginB complex

Summary for 8QVU

• Entry DOI: 10.2210/pdb8qvu/pdb
• Descriptor: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (9 entities in total)
• Functional Keywords: ternary complex, protac, degrader, e3 ligase, ligase, gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 139879.16

Authors

Wijaya, A.J.,Zollman, D.,Farnaby, W.,Ciulli, A. (deposition date: 2023-10-18, release date: 2023-12-06, Last modification date: 2024-10-02)

Primary citation

Popow, J.,Farnaby, W.,Gollner, A.,Kofink, C.,Fischer, G.,Wurm, M.,Zollman, D.,Wijaya, A.,Mischerikow, N.,Hasenoehrl, C.,Prokofeva, P.,Arnhof, H.,Arce-Solano, S.,Bell, S.,Boeck, G.,Diers, E.,Frost, A.B.,Goodwin-Tindall, J.,Karolyi-Oezguer, J.,Khan, S.,Klawatsch, T.,Koegl, M.,Kousek, R.,Kratochvil, B.,Kropatsch, K.,Lauber, A.A.,McLennan, R.,Olt, S.,Peter, D.,Petermann, O.,Roessler, V.,Stolt-Bergner, P.,Strack, P.,Strauss, E.,Trainor, N.,Vetma, V.,Whitworth, C.,Zhong, S.,Quant, J.,Weinstabl, H.,Kuster, B.,Ettmayer, P.,Ciulli, A.
Targeting cancer with small-molecule pan-KRAS degraders.
Science, 385:1338-1347, 2024

PubMed Abstract: Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

PubMed: 39298590
DOI: 10.1126/science.adm8684

Experimental method

X-RAY DIFFRACTION (2.24 Å)