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作者：SCI天天读
SCI
25 May 2024
D3S-001, a KRAS G12C inhibitor with rapid target engagement kinetics, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities
(Cancer Discovery, IF: 29.1)
Jing Zhang, Sun Min Lim2, Mi Ra Yu, Cheng Chen, Jia Wang, Wenqian Wang, Haopeng Rui, Jingtao Lu, Shun Lu, Tony Mok, Zhi Jian Chen1 and Byoung Chul Cho
CORRESPONDENCE TO: George.chen@d3bio.com, CBC1971@yuhs.ac
Abstract 摘要
First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic “cycling” of KRAS between its GDP- and GTP-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report D3S-001, a next generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as EGF and HGF, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S- 001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S- 001 contributed to robust anti-tumor activity preclinically and translated into promising clinical activity in an ongoing phase 1 trial (NCT05410145).
第一代KRAS G12C抑制剂，如Sotorasib和Adagrasib，受到临床反应深度和持续时间的限制。对其中度临床活性的一个可能得解释是KRAS在其GDP和GTP结合状态之间的动态“循环”，引发了关于靶向GDP结合形式是否可以完全阻断这种致癌驱动因素的争议。我们在此报道了D3S-001，一种具有更快靶点结合（TE）动力学的新一代GDP结合形式G12C抑制剂，在纳摩尔浓度下耗尽细胞活性KRAS G12C。在生长因子（如EGF和HGF）存在的情况下，Sotorasib和Adagrasib抑制KRAS的能力受到损害，而D3S-001的TE动力学几乎不受影响，这是D3S-001与其他GDP结合的G12C抑制剂不同的独特特征。此外，D3S-001的高共价效力和细胞TE效率在临床前有助于增强抗肿瘤活性，并在正在进行的1期试验中表现出有希望的临床活性（NCT05410145）。
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