ScholarWorks@숙명여자대학교

초록

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 mu M) and 29 (PAK4 IC50 1.88 mu M) demonstrated comparable enzymatic potency, consistent with ATP-competitive inhibition, while compound 29 was effective in inhibiting cancer cell proliferation (HCT-116 GI50 23.0 mu M; A549 GI50 11.3 mu M). In conclusion, this study highlights the potential of targeting underexplored subpockets in PAK4 and provides new molecular insights for the discovery of PAK4 inhibitors.

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