Mukd‑546 (chemical name: ) is a novel heterocyclic scaffold derived from a structure‑based design campaign targeting the allosteric pocket of MEK1. Preliminary SAR (structure‑activity relationship) studies indicated that the sulfonyl‑pyrimidine core confers high affinity while the 4‑fluorophenyl substituent enhances metabolic stability.
Mukd‑546: Pre‑clinical Evaluation of a Novel Small‑Molecule Inhibitor of the MAPK/ERK Pathway for Targeted Cancer Therapy mukd-546
A. Patel¹, J. Liu², M. García³, S. K. Singh¹, L. R. Thompson⁴, H. Kim⁵ Mukd‑546 (chemical name: ) is a novel heterocyclic
Docking studies revealed a nanomolar‑range binding energy (ΔG = –11.2 kcal·mol⁻¹) within the ATP‑binding pocket of MEK1. In vitro kinase assays confirmed a mean IC₅₀ of 8 nM against MEK1/2, with >200‑fold selectivity over a panel of 30 off‑target kinases. Mukd‑546 reduced viability of KRAS‑mutant PDAC (MIA‑PaCa‑2, IC₅₀ = 45 nM) and BRAF‑mutant melanoma (A375, IC₅₀ = 28 nM) cells, induced G₁ arrest, and triggered caspase‑3/7‑mediated apoptosis. In rats, oral administration (10 mg·kg⁻¹) yielded a bioavailability of 62 % and a half‑life of 6.3 h. In xenograft models, daily oral dosing (30 mg·kg⁻¹) for 21 days produced tumor growth inhibition (TGI) of 84 % in PDAC and 78 % in melanoma, with no significant weight loss or histopathological toxicity. Patel¹, J
Mukd‑546 exhibits potent, selective MEK inhibition, favorable pharmacokinetics, and robust antitumor activity in pre‑clinical models. These data support further development of Mukd‑546 as a candidate for clinical evaluation in MAPK‑driven malignancies.