8V3A

Crystal structure of KRAS-G12C (GDP-bound) in complex with BBO-8520

8V3A の概要

• エントリーDOI: 10.2210/pdb8v3a/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: kras, ras, k-ras, kras4b, inhibitor, bbo8520, bbo-8520, bbo, theras, bridgebio, oncoprotein, oncoprotein-inhibitor complex, oncoprotein/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 41116.19

構造登録者

Chan, A.H.,Bratcher, D.R.,Simanshu, D.K. (登録日: 2023-11-27, 公開日: 2024-12-18, 最終更新日: 2025-03-12)

主引用文献

Maciag, A.E.,Stice, J.P.,Wang, B.,Sharma, A.K.,Chan, A.H.,Lin, K.,Singh, D.,Dyba, M.,Yang, Y.,Setoodeh, S.,Smith, B.P.,Ju, J.H.,Jeknic, S.,Rabara, D.,Zhang, Z.,Larsen, E.K.,Esposito, D.,Denson, J.P.,Ranieri, M.,Meynardie, M.,Mehdizadeh, S.,Alexander, P.A.,Abreu Blanco, M.,Turner, D.M.,Xu, R.,Lightstone, F.C.,Wong, K.K.,Stephen, A.G.,Wang, K.,Simanshu, D.K.,Sinkevicius, K.W.,Nissley, D.V.,Wallace, E.,McCormick, F.,Beltran, P.J.
Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C.
Cancer Discov, 15:578-594, 2025

PubMed Abstract: Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor-activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer. Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic. See related commentary by Zhou and Westover, p. 455.

PubMed: 39642212
DOI: 10.1158/2159-8290.CD-24-0840

実験手法

X-RAY DIFFRACTION (1.67 Å)