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.
Mukd‑546: Pre‑clinical Evaluation of a Novel Small‑Molecule Inhibitor of the MAPK/ERK Pathway for Targeted Cancer Therapy mukd-546
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. University of Cambridge
A. Patel (email: a.patel@cam.ac.uk) Abstract Background: The MAPK/ERK signaling cascade is frequently hyper‑activated in a wide spectrum of solid tumours, driving uncontrolled proliferation and resistance to conventional chemotherapy. Mukd‑546, a newly synthesized heterocyclic small‑molecule, was designed to selectively inhibit MEK1/2, the central kinases of this pathway. UK ² Institute of Molecular Medicine
A. Patel¹, J. Liu², M. García³, S. K. Singh¹, L. R. Thompson⁴, H. Kim⁵
Mukd‑546; MEK inhibitor; MAPK/ERK pathway; pre‑clinical oncology; targeted therapy; KRAS; BRAF 1. Introduction The MAPK/ERK cascade (RAS‑RAF‑MEK‑ERK) orchestrates critical cellular processes such as proliferation, differentiation, and survival. Aberrant activation—most commonly via KRAS, NRAS, or BRAF mutations—underpins the pathogenesis of >30 % of human cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal carcinoma, and melanoma. While several MEK inhibitors (e.g., trametinib, binimetinib) have entered clinical practice, therapeutic efficacy is limited by dose‑dependent toxicities and rapid emergence of resistance (e.g., MAPK re‑activation, feedback loops). Consequently, there remains a pressing need for next‑generation MEK inhibitors with improved potency, selectivity, and pharmacologic properties.
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