Mukd-546 📥

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

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. mukd-546

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

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. In rats, oral administration (10 mg·kg⁻¹) yielded a

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.

A. Patel¹, J. Liu², M. García³, S. K. Singh¹, L. R. Thompson⁴, H. Kim⁵ These data support further development of Mukd‑546 as

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.