Discovery of Novel ERK5 Inhibitors for Pancreatic Cancer via a Virtual Screening Approach.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a dismal prognosis, with limited therapeutic options beyond first-line chemotherapy. Extracellular signal-regulated kinase 5 (ERK5) represents a compelling therapeutic target, particularly due to its compensatory role in sustaining proliferation and MYC stability following ERK1/2 inhibition in KRAS-mutant PDAC. To address the need for novel inhibitors, we implemented an integrated virtual screening workflow combining PSICHIC screening, KarmaDock, similarity analysis, molecular clustering, and manual selection. This strategy identified four structurally distinct ERK5-targeting candidates. Among these, compounds 1 and 2 inhibited ERK5 kinase activity with IC50 values of 416.4 and 991.3 nM, respectively. Compound 1 demonstrated potent antiproliferative effects on PDAC cell lines (PANC-1: IC50 = 1199.0 nM; MiaPaCa-2: IC50 = 62.5 nM; AsPC-1: IC50 = 199.9 nM). Molecular dynamics simulations revealed stabilization of the ERK5-compound 1 complex through hydrogen bonding with hinge residues MET-96 and ASP-94. These results establish compound 1 as a promising lead compound, providing a novel chemical scaffold for the development of ERK5-targeted therapies against PDAC.