TY - JOUR
T1 - Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader
AU - Wei, Jieli
AU - Hu, Jianping
AU - Wang, Li
AU - Xie, Ling
AU - Jin, Margaret S.
AU - Chen, Xian
AU - Liu, Jing
AU - Jin, Jian
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/12/12
Y1 - 2019/12/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076414460&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b01528
DO - 10.1021/acs.jmedchem.9b01528
M3 - Article
C2 - 31730343
AN - SCOPUS:85076414460
SN - 0022-2623
VL - 62
SP - 10897
EP - 10911
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 23
ER -