发现MRTX1133前药作为KRAS突变型癌症的口服疗法
Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS Mutation.
作者信息
Ji Xiang, Li Yan, Kong Xianqi, Chen Dawei, Lu Jiasheng
机构信息
Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai 200437, China.
Risen (Shanghai) Pharma Tech Co., Ltd., Shanghai 201210, China.
出版信息
ACS Omega. 2023 Feb 9;8(7):7211-7221. doi: 10.1021/acsomega.3c00329. eCollection 2023 Feb 21.
Effective oral therapies are urgently required to treat KRAS mutant cancers. Therefore, synthesis and screening were performed for 38 prodrugs of MRTX1133 to identify an oral prodrug of MRTX1133, a KRAS mutant protein-specific inhibitor. and evaluations revealed prodrug as the first orally available KRAS inhibitor. Prodrug exhibited improved pharmacokinetic properties for the parent compound in mice and was efficacious in a KRAS mutant xenograft mouse tumor model after oral administration.
迫切需要有效的口服疗法来治疗KRAS突变型癌症。因此，对MRTX1133的38种前药进行了合成和筛选，以鉴定MRTX1133（一种KRAS突变蛋白特异性抑制剂）的口服前药。评估显示前药是第一种口服可用的KRAS抑制剂。前药在小鼠体内对母体化合物表现出改善的药代动力学特性，并且在口服给药后对KRAS突变异种移植小鼠肿瘤模型有效。
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