KRAS inhibitors: going noncovalent

被引：10

作者：

Drosten, Matthias ^{[1
,4
,5
]}

Barbacid, Mariano ^{[2
,3
,6
]}

机构：

[1] Ctr Invest Canc CIC, Mol Mech Canc Program, Salamanca, Spain

[2] CSIC USAL, Inst Biologia Mol & Celular Canc IBMCC, Salamanca, Spain

[3] Ctr Nacl Invest Oncol CNIO, Mol Oncol Program, Madrid, Spain

[4] Ctr Investigaciondel Canc CIC, Mech Canc Program, Campus Unamuno S-N, Salamanca 37007, Spain

[5] CSIC USAL, Inst Biologia Mol & Celular Canc IBMCC, Campus Unamuno S-N, Salamanca 37007, Spain

[6] Ctr Nacl Invest Oncol CNIO, Mol Oncol Program, Melchor Fernandez Almagro 3, Madrid 28029, Spain

来源：

MOLECULAR ONCOLOGY | 2022年 / 16卷 / 22期

基金：

欧洲研究理事会;

关键词：

colorectal cancer; combination therapies; KRAS(G12D); noncovalent binding; pancreatic ductal adenocarcinoma; KRAS(G12C); INHIBITION;

D O I：

10.1002/1878-0261.13341

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

KRAS(G12D) is the most frequent KRAS mutation in human cancer with particularly high frequencies in pancreatic and colorectal cancer. Informed by the structure of the KRAS(G12C) inhibitor adagrasib, Hallin et al. have now, through multiple rounds of structure-based drug design, identified and validated a potent, selective, and noncovalent KRAS(G12D) inhibitor, MRTX1133. This study demonstrated that MRTX1133 inhibited both the inactive and active state of KRAS(G12D) and showed potent antitumor activity in several preclinical models of pancreatic and colorectal cancer, especially when combined with cetuximab, a monoclonal antibody against the EGFR, or BYL-719, a potent PI3K alpha inhibitor.

引用

页码：3911 / 3915

页数：5

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