Mukd-546 [hot] -

A. Patel (email: a.patel@cam.ac.uk)

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

Cells were seeded at 5 × 10³ cells well⁻¹ in 96‑well plates, treated with Mukd‑546 (0.1 nM–10 µM) for 72 h, and MTT (0.5 mg·mL⁻¹) added for 4 h. Absorbance at 570 nm measured cell viability. IC₅₀ values calculated using non‑linear regression (GraphPad Prism). Cells were seeded at 5 × 10³ cells

Mice were randomized (Day 7, when tumors reached ~100 mm³) to receive either vehicle (0.5 % methylcellulose) or Mukd‑546 (30 mg·kg⁻¹, oral gavage, QD) for 21 days. Tumor volumes measured twice weekly (V = ½ × length × width²). Body weight and clinical signs monitored. At endpoint, tumors were harvested for immunohistochemistry (IHC) of p‑ERK and Ki‑67. Mice were randomized (Day 7, when tumors reached

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.