Chemical induced protein knockdown via the proteolysis targeting chimera (PROTAC) technology is a promising approach to target dysregulated proteins. Moreover, MEK1/2 proteins are the only RAF substrates. MEK1/2 proteins are the crucial “gatekeepers” of ERK activity. The classic RAS-RAF-MEK-ERK signaling pathway is common in mammals, plays critical roles in multiple cellular processes. Furthermore, it includes cell cycle progression, cell proliferation, apoptosis, cell differentiation, cell metabolism, and cell migration. Hyperactivation of ERK signaling due to mutations in genes encoding RTKs, RAS, BRAF, CRAF, MEK1 or MEK2 causes about 30% of human cancers. Nonetheless, Deregulation of this pathway is mainly driven by mutations of BRAF and its activator RAS. Thus, inhibitors targeting MEK proteins specifically suppress the ERK signaling output without affecting other signal transduction cascades directly. MS432 is a first-in-class and highly selective PD0325901-based VHL-recruiting PROTAC degrader for MEK1 and MEK2 with good anti-cancer activity.

MS432 is a first-in-class and highly selective PD0325901-based VHL-recruiting PROTAC degrader for MEK1 and MEK2. Specifically, MS432 displays good plasma exposure in mice and exhibits DC₅₀ values of 31 nM and 17 nM for MEK1, MEK2 in HT29 cells respectively. Besides, MS432 potently and selectively degraded MEK1/2 in a VHL E3 ligase- and proteasome-dependent manner and suppressed ERK phosphorylation in cells. In addition, MS432 inhibited colorectal cancer and melanoma cell proliferation much more effectively. Furthermore, MS432 inhibited ERK signaling and suppressed cancer cell proliferation much more effectively. Finally, MS432 displays good plasma exposure in mice and is useful in vivo efficacy studies. All in all, MS432 is a first-in-class and highly selective PD0325901-based VHL-recruiting PROTAC degrader for MEK1 and MEK2 with good anti-cancer activity.