Structure-guided discovery of 6-aminopyridine derivatives for group II PAK4 inhibition
- Bioorg Chem. 2026 Mar:170:109470. doi: 10.1016/j.bioorg.2026.109470.
- 1. College of Pharmacy, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Republic of Korea.
- 2. Laboratory Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungcheongbuk-do 28116, Republic of Korea.
- 3. College of Pharmacy, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Republic of Korea. Electronic address: [email protected].
p21-Activated kinase 4 (PAK4) is a Group II serine/threonine kinase implicated in tumor growth and immune evasion, and is therefore a promising target for Anticancer therapy. Leveraging structure-guided design, we report a novel series of 6-aminopyridine derivatives that target a previously underexplored deep hydrophobic subpocket adjacent to Phe461, which extends from the floor pocket of PAK4. Even with a relatively concise compound set, the focused SAR study identified key substituent features required for deep-pocket engagement, and subsequent molecular docking and dynamics simulations supported an underexploited binding mode centered on the key residue Phe461. Among the synthesized compounds, 17 (PAK4 IC₅₀ 0.71 μM) and 29 (PAK4 IC₅₀ 1.88 μM) demonstrated comparable enzymatic potency, consistent with ATP-competitive inhibition, while compound 29 was effective in inhibiting Cancer cell proliferation (HCT-116 GI₅₀ 23.0 μM; A549 GI50 11.3 μM). In conclusion, this study highlights the potential of targeting underexplored subpockets in PAK4 and provides new molecular insights for the discovery of PAK4 inhibitors.