Structure-Guided Discovery and Preclinical Assessment of Novel (Thiophen-3-yl)aminopyrimidine Derivatives as Potent ERK1/2 Inhibitors

The RAS-RAF-MEK-ERK signaling cascade is abnormally activated
in
various tumors, playing a crucial role in mediating tumor progression.
As the key component at the terminal stage of this cascade, ERK1/2
emerges as a potential antitumor target and offers a promising therapeutic
strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent
ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful
ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM)
and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal
cancer models harboring BRAF and RAS mutations. 36c could
directly inhibit ERK1/2, significantly block the phosphorylation expression
of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis
and incomplete autophagy-related cell death. Taken together, this
work provides a promising ERK1/2 lead compound for multiple tumor-treatment
drug discovery.