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Published on: November 9, 2020
Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D
Chuan Zhou1, Zisheng Fan2,3,4, Yuejiao Gu1,5
1Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Abstract:
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.
Insights
Researchers developed novel KRASG12D Proteolysis Targeting Chimeras (PROTACs) that effectively degrade the KRASG12D oncoprotein. Compound 8o demonstrated potent antitumor activity in preclinical models, offering a promising new cancer therapy strategy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- KRASG12D mutations are prevalent in many cancers, driving tumor growth.
- Targeting KRASG12D presents a significant therapeutic challenge.
- Proteolysis Targeting Chimeras (PROTACs) offer a novel approach to protein degradation.
Purpose of the Study:
- To design, synthesize, and evaluate novel KRASG12D PROTACs.
- To investigate the structure-activity relationships of these PROTACs.
- To assess the therapeutic potential of optimized KRASG12D PROTACs in preclinical cancer models.
Main Methods:
- Synthesis of KRASG12D PROTACs by conjugating MRTX1133 analogues with VHL ligands.
- Evaluation of membrane permeability and degradation activity.
- Mechanism of action studies using compound 8o.
- In vitro cancer cell growth inhibition assays.
- In vivo pharmacokinetic, pharmacodynamic, and antitumor efficacy studies in mouse models.
Main Results:
- Structural modifications, particularly linker optimization, significantly impacted PROTAC membrane permeability and degradation efficacy.
- Compound 8o demonstrated potent, rapid, and selective KRASG12D degradation via VHL and proteasome.
- Compound 8o effectively suppressed KRASG12D mutant cancer cell proliferation.
- Favorable pharmacokinetic and pharmacodynamic profiles were observed for compound 8o in mice.
- Significant antitumor efficacy was achieved with compound 8o in an AsPC-1 xenograft model.
Conclusions:
- KRASG12D PROTACs, exemplified by compound 8o, represent a viable therapeutic strategy.
- Optimized PROTACs can achieve potent and selective degradation of KRASG12D.
- Compound 8o shows promise as a complementary therapy for KRASG12D-driven cancers.
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