PMD-026 is a first-in-class, orally bioavailable, selective p90 ribosomal S6 kinase (RSK) inhibitor with potent anticancer activity, particularly against triple-negative breast cancer (TNBC). In biochemical assays, PMD-026 inhibits RSK1–4 with IC50 values of 0.7–2 nM and shows good selectivity in kinome-wide profiling. In TNBC cell lines, PMD-026 suppresses anchorage-independent growth with IC50 values of 0.2–6.2 µM and anchorage-dependent proliferation with IC50 values of 1.8–8.4 µM, while inducing apoptosis and reducing phosphorylation of the downstream biomarker YB-1. In vivo, PMD-026 produced 72% tumor growth inhibition in MDA-MB-231 xenografts and 73% tumor regression in MDA-MB-468 xenografts. PMD-026 also demonstrated synergistic antitumor activity with paclitaxel, doxorubicin, fulvestrant, and enzalutamide in preclinical models, supporting its potential applications in RSK-targeted cancer research, TNBC, hormone-resistant breast cancer, prostate cancer, melanoma, and hematologic malignancies.
