2. Academic Validation
  3. Discovery of KRAS-G12D degraders via exploration of various E3 ligases

Discovery of KRAS-G12D degraders via exploration of various E3 ligases

  • Eur J Med Chem. 2026 Apr 5:307:118635. doi: 10.1016/j.ejmech.2026.118635.
Hyerin Yim 1,  Xiangyang Song 1,  Yue Zhong 1,  Jacqueline Hu 1,  Yan Xiong 2,  Jian Jin 3
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 2 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Electronic address: yan.xiong@mssm.edu.
  • 3 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Electronic address: jian.jin@mssm.edu.
PMID: 41679196 DOI: 10.1016/j.ejmech.2026.118635
Abstract

PROteolysis TArgeting Chimera (PROTAC) is a promising modality for targeted protein degradation. Although 600+ E3 Ligases exist in the human genome, most PROTACs exploit a very limited set of E3 Ligases, primarily CRBN and VHL. In this study, we designed, synthesized and evaluated a series of KRAS-G12D degraders that recruit one of four E3 Ligases (CRBN, VHL, DCAF1, or KLHDC2) using a common KRAS-G12D binder derived from the KRAS-G12D inhibitor MRTX1133. Through this structure-activity relationship (SAR) study, we discovered two potent degraders: 30 (CRBN-based) and 41 (VHL-based), both of which effectively degraded KRAS-G12D and suppressed downstream signaling. By introducing a triazole-based VHL ligand, we subsequently discovered 43, which showed improved degradation and antiproliferative activity comparable to a previously reported KRAS-G12D degrader. In contrast, KLHDC2- and DCAF1-based degraders failed to induce KRAS-G12D degradation, potentially due to suboptimal ternary complex formation or insufficient E3 Ligase compatibility. These findings highlight the importance of E3 Ligase selection in the development of effective KRAS-G12D degraders.

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