2. Academic Validation
  3. Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader

Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader

  • J Med Chem. 2019 Dec 12;62(23):10897-10911. doi: 10.1021/acs.jmedchem.9b01528.
Jieli Wei 1,  Jianping Hu 1,  Li Wang 2,  Ling Xie 2,  Margaret S Jin 1,  Xian Chen 2,  Jing Liu 1,  Jian Jin 1
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
  • 2 Department of Biochemistry and Biophysics , University of North Carolina at Chapel Hill , Chapel Hill , North Carolina 27599 , United States.
PMID: 31730343 DOI: 10.1021/acs.jmedchem.9b01528
Abstract

MEK1 and MEK2 (also known as MAP2K1 and MAP2K2) are the "gatekeepers" of the ERK signaling output with redundant roles in controlling ERK activity. Numerous inhibitors targeting MEK1/2 have been developed including three FDA-approved drugs. However, acquired resistance to MEK1/2 inhibitors has been observed in patients, and new therapeutic strategies are needed to overcome the resistance. Here, we report a first-in-class degrader of MEK1/2, MS432 (23), which potently and selectively degraded MEK1 and MEK2 in a VHL E3 ligase- and proteasome-dependent manner and suppressed ERK phosphorylation in cells. It inhibited colorectal Cancer and melanoma cell proliferation much more effectively than its negative control MS432N (24), and its effect was phenocopied by MEK1/2 knockdown. Compound 23 was highly selective for MEK1/2 in global proteomic profiling studies. It was also bioavailable in mice and can be used for in vivo efficacy studies. We provide two well-characterized chemical tools to the biomedical community.

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