Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS^G12D

Abstract

KRAS G12D , the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRAS G12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRAS G12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRAS G12D induced by 8o was via a VHL-and proteasomedependent manner. This compound selectively and potently suppressed the growth of multiple KRAS G12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRAS G12D -driven cancers as the complementary therapeutic strategy to KRAS inhibition.

Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search

“…2,6 Several PROTACs have recently been designed for drug development. [8][9][10][11][12][13][14][15] During the formation of the ternary complex, the E3 ligand and warhead in the PROTAC substructures bind to the E3 ligase and target protein, respectively. These ligands determine the affinity of the PROTAC for proteins, and these substructures can be identified using approaches similar to those used for traditional small-molecule drugs, such as virtual screening and highthroughput screening.…”

Development of PROTACS degrading KRAS and SOS1

“…A series of KRAS G12D PROTACs have been developed by coupling MRTX1133 analogs and VHL to target the most frequent KRAS mutation [ 28 , 29 ]. Variations of the linker group and the KRAS inhibitor MRTX1133 demonstrated the dependency of the PROTAC activity on the cell membrane permeability.…”