Structure-Based Design of 6‑Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

Herein, we report the discovery and
characterization of a novel
class of PAK4 inhibitors with a quinazoline scaffold. Based on the
shape and chemical composition of the ATP-binding pocket of PAKs,
we chose a 2,4-diaminoquinazoline series of inhibitors as a starting
point. Guided by X-ray crystallography and a structure-based drug
design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide
PAK4 inhibitors were designed and synthesized. The inhibitors’
selectivity, therapeutic potency, and pharmaceutical properties were
optimized. One of the best compounds, 31 (CZh226), showed
remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase
selectivity profile. Moreover, this compound potently inhibited the
migration and invasion of A549 tumor cells by regulating the PAK4-directed
downstream signaling pathways in vitro. Taken together,
these data support the further development of 31 as a
lead compound for PAK4-targeted anticancer drug discovery and as a
valuable research probe for the further biological investigation of
group II PAKs.