Mukd-546 May 2026

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.

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

A multi‑stage pre‑clinical program was conducted: (i) in‑silico docking and molecular dynamics to predict binding affinity; (ii) biochemical kinase assays to assess selectivity; (iii) cellular viability, apoptosis, and cell‑cycle analyses in a panel of 12 cancer cell lines; (iv) pharmacokinetic (PK) profiling in Sprague‑Dawley rats; (v) efficacy and safety evaluation in xenograft mouse models of KRAS‑mutant pancreatic ductal adenocarcinoma (PDAC) and BRAF‑mutant melanoma. In rats, oral administration (10 mg·kg⁻¹) yielded a

A. Patel¹, J. Liu², M. García³, S. K. Singh¹, L. R. Thompson⁴, H. Kim⁵ ¹ Department of Pharmacology

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.

¹ Department of Pharmacology, University of Cambridge, UK ² Institute of Molecular Medicine, Shanghai Jiao Tong University, China ³ Center for Cancer Research, Universidad Nacional Autónoma de México, Mexico ⁴ Department of Chemistry, University of California, San Diego, USA ⁵ Division of Oncology, Seoul National University Hospital, South Korea

Mukd‑546: Pre‑clinical Evaluation of a Novel Small‑Molecule Inhibitor of the MAPK/ERK Pathway for Targeted Cancer Therapy