D-1553：一种新型 KRASG12C 抑制剂，具有有效、选择性的细胞和体内抗肿瘤活性,Cancer Science

当前位置： X-MOL 学术 › Cancer Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

D-1553：一种新型 KRASG12C 抑制剂，具有有效、选择性的细胞和体内抗肿瘤活性
Cancer Science ( IF 4.5 ) Pub Date : 2023-05-09 , DOI: 10.1111/cas.15829
Zhe Shi ₁ , Jifang Weng ₁ , Haotao Niu ₁ , Hong Yang ₁ , Rongfeng Liu ₁ , Yan Weng ₁ , Qingqing Zhu ₁ , Yihong Zhang ₁ , Liangshan Tao ₁ , Zhenwu Wang ₁ , Seok Jae Huh ₂ , Yueheng Jiang ₁ , Hong Mei ₁ , Xing Dai ₁ , Ling Zhang ₁ , Yaolin Wang ₁

Affiliation

D-1553是一种选择性靶向KRAS ^G12C的小分子抑制剂，目前正在进行II期临床试验。在这里，我们报告了证明 D-1553 抗肿瘤活性的临床前数据。通过热位移测定和 KRAS ^G12C偶联核苷酸交换测定测定D-1553 抑制 GDP 结合的 KRAS ^{G12C突变的效力和特异性。}^{在 KRAS G12C}突变癌细胞和异种移植模型中评估了 D-1553 单独或与其他疗法联合的体外和体内抗肿瘤活性。D-1553 对突变的 GDP 结合 KRAS ^G12C蛋白表现出选择性和有效的活性。D-1553 选择性抑制含有 KRAS ^{G12C的 NCI-H358 细胞中的 ERK 磷酸化}突变。与KRAS WT和KRAS ^G12D细胞系相比，D-1553选择性抑制多种KRAS ^G12C细胞系的细胞活力，且效力略优于sotorasib和adagrasib。在一组异种移植肿瘤模型中，口服 D-1553 显示出部分或完全的肿瘤消退。与单独使用 D-1553 相比，D-1553 与化疗、MEK 抑制剂或 SHP2 抑制剂的组合对肿瘤生长抑制或消退显示出更强的效力。这些发现支持 D-1553 作为一种有效候选药物的临床评估，无论是作为单一药物还是联合用药，用于治疗携带 KRAS ^G12C突变的实体瘤患者。

"点击查看英文标题和摘要"

D-1553: A novel KRASG12C inhibitor with potent and selective cellular and in vivo antitumor activity

D-1553 is a small molecule inhibitor selectively targeting KRAS^G12C and currently in phase II clinical trials. Here, we report the preclinical data demonstrating antitumor activity of D-1553. Potency and specificity of D-1553 in inhibiting GDP-bound KRAS^G12C mutation were determined by thermal shift assay and KRAS^G12C-coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRAS^G12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRAS^G12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRAS^G12C mutation. Compared to the KRAS WT and KRAS^G12D cell lines, D-1553 selectively inhibited cell viability in multiple KRAS^G12C cell lines, and the potency was slightly superior to sotorasib and adagrasib. In a panel of xenograft tumor models, D-1553, given orally, showed partial or complete tumor regression. The combination of D-1553 with chemotherapy, MEK inhibitor, or SHP2 inhibitor showed stronger potency on tumor growth inhibition or regression compared to D-1553 alone. These findings support the clinical evaluation of D-1553 as an efficacious drug candidate, both as a single agent or in combination, for patients with solid tumors harboring KRAS^G12C mutation.

更新日期：2023-05-09

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南