Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRASG12D Mutation

Xiang Ji; Yan Li; Xianqi Kong; Dawei Chen; Jiasheng Lu

doi:10.1021/acsomega.3c00329

Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRAS^G12D Mutation

ACS Omega. 2023 Feb 9;8(7):7211-7221. doi: 10.1021/acsomega.3c00329. eCollection 2023 Feb 21.

Authors

Xiang Ji^{1

2}, Yan Li², Xianqi Kong², Dawei Chen², Jiasheng Lu^{2

3}

Affiliations

¹ Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai 200437, China.
² Risen (Shanghai) Pharma Tech Co., Ltd., Shanghai 201210, China.
³ Guangdong Key Laboratory of Nanomedicine, Chinese Academy of Sciences, Shenzhen 518055, China.

Abstract

Effective oral therapies are urgently required to treat KRAS^G12D mutant cancers. Therefore, synthesis and screening were performed for 38 prodrugs of MRTX1133 to identify an oral prodrug of MRTX1133, a KRAS^G12D mutant protein-specific inhibitor. In vitro and in vivo evaluations revealed prodrug 9 as the first orally available KRAS^G12D inhibitor. Prodrug 9 exhibited improved pharmacokinetic properties for the parent compound in mice and was efficacious in a KRAS^G12D mutant xenograft mouse tumor model after oral administration.