3 research outputs found
Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<sup>G12D</sup>
KRASG12D, 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 KRASG12D 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 KRASG12D PROTACs. Mechanism studies with
the representative compound 8o demonstrated that the
potent, rapid, and selective degradation of KRASG12D induced
by 8o was via a VHL- and proteasome-dependent manner.
This compound selectively and potently suppressed the growth of multiple
KRASG12D 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 KRASG12D-driven cancers as the complementary
therapeutic strategy to KRAS inhibition
Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<sup>G12D</sup>
KRASG12D, 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 KRASG12D 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 KRASG12D PROTACs. Mechanism studies with
the representative compound 8o demonstrated that the
potent, rapid, and selective degradation of KRASG12D induced
by 8o was via a VHL- and proteasome-dependent manner.
This compound selectively and potently suppressed the growth of multiple
KRASG12D 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 KRASG12D-driven cancers as the complementary
therapeutic strategy to KRAS inhibition
Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<sup>G12D</sup>
KRASG12D, 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 KRASG12D 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 KRASG12D PROTACs. Mechanism studies with
the representative compound 8o demonstrated that the
potent, rapid, and selective degradation of KRASG12D induced
by 8o was via a VHL- and proteasome-dependent manner.
This compound selectively and potently suppressed the growth of multiple
KRASG12D 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 KRASG12D-driven cancers as the complementary
therapeutic strategy to KRAS inhibition