Maciag Anna E, Stice James P, Wang Bin, Sharma Alok K, Chan Albert H, Lin Ken, Singh Devansh, Dyba Marcin, Yang Yue, Setoodeh Saman, Smith Brian P, Ju Jin Hyun, Jeknic Stevan, Rabara Dana, Zhang Zuhui, Larsen Erik K, Esposito Dominic, Denson John-Paul, Ranieri Michela, Meynardie Mary, Mehdizadeh Sadaf, Alexander Patrick A, Abreu Blanco Maria, Turner David M, Xu Rui, Lightstone Felice C, Wong Kwok-Kin, Stephen Andrew G, Wang Keshi, Simanshu Dhirendra K, Sinkevicius Kerstin W, Nissley Dwight V, Wallace Eli, McCormick Frank, Beltran Pedro J
NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
BridgeBio Oncology Therapeutics, South San Francisco, California.
Cancer Discov. 2025 Mar 3;15(3):578-594. doi: 10.1158/2159-8290.CD-24-0840.
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.
已获批的KRASG12C抑制剂通过隔离无活性的、结合GDP的（关闭）形式来阻止致癌激活，而非直接结合并抑制活性的、结合GTP的（开启）形式。这种方法无法直接作用于活性蛋白。不出所料，与KRASG12C（开启）的表达和活性增加相关的情况下，会观察到对仅针对KRASG12C（关闭）形式抑制剂的适应性耐药。为了实现对KRASG12C的最佳靶向覆盖，我们研发了BBO - 8520，这是一种一流的、直接针对KRASG12C（开启）和（关闭）形式的双重抑制剂。BBO - 8520结合在开关II/螺旋3口袋中，共价修饰靶半胱氨酸，并阻止效应物与KRASG12C（开启）结合。BBO - 8520在生长因子激活状态下表现出强大的信号抑制作用，而目前仅针对（关闭）形式的抑制剂在此状态下几乎没有可测量的活性。在体内，BBO - 8520显示出快速的靶点结合和信号抑制，在多个模型中导致持久的肿瘤消退，包括那些对仅针对KRASG12C（关闭）形式抑制剂耐药的模型。BBO - 8520正在KRASG12C非小细胞肺癌患者中进行1期临床试验。意义：BBO - 8520是一种一流的直接小分子共价双重抑制剂，能与处于活性（开启）和无活性（关闭）构象的KRASG12C结合。BBO - 8520代表了一种新的作用机制，可实现最佳的靶点覆盖，并延缓临床上仅针对（关闭）形式抑制剂所出现的适应性耐药的出现。见周和韦斯托弗的相关评论，第455页。
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