조병철 (연세대학교 의과대학)

한빛사논문

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연세대학교 의과대학

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Cancer Discov., May 08 2024, | https://doi.org/10.1158/2159-8290.CD-24-0006 D3S-001, a KRAS G12C inhibitor with rapid target engagement kinetics, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities

Jing Zhang^1*, Sun Min Lim^2*, Mi Ra Yu³, Cheng Chen¹, Jia Wang¹, Wenqian Wang¹, Haopeng Rui¹, Jingtao Lu¹, Shun Lu⁴, Tony Mok⁵, Zhi Jian Chen1# and Byoung Chul Cho^2#

¹D3 Bio (Wuxi) Co. Ltd, Shanghai, China

²Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

³Yonsei New II Han Institute for Integrative Lung Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

⁴Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

⁵State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China

^*Equal lead author contributions

^#Equal senior author contributions and co-corresponding authors

Corresponding Author : Byoung C. Cho

Abstract

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).

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-09)
연구진국내(교신)+국외 연구진
분야 의약학 > 종양의학

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