Structure-Based PAK4 Inhibitor Discovery for Antitumor Drug Development

DRA lecture held by Professor Maosheng Cheng, Shenyang Pharmaceutical University, China

Professor Maosheng Cheng is the president of Shenyang Pharmaceutical University in Shenyang, China. He is currently also the director of the Key Laboratory of Structure-Based Drug Design and Discovery (Ministry of Education) at Shenyang Pharmaceutical University. His research interests are discovery of bioactive molecules and development of drug candidates.

PAK4 (p21-activated kinase 4) is an enzyme in the human body belonging to a family of proteins called serine/threonine kinases. PAK4 plays a crucial role in various cellular processes, making it important for both health and disease. In this talk, he will introduce the discovery and characterization of PAK4 inhibitors developed in his group over the years by utilizing computer-aided drug design methods and structure-based drug design (SBDD) approach.

As an example, a 2,4-diaminoquinazoline series of inhibitors were chosen as the starting points. Guided by X-ray crystallography and SBDD, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors selectivity, therapeutic potency, and pharmaceutical properties were optimized. Compound 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. Compound CZh226 could be further developed 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.

The lecture is organized on behalf of the graduate programme in pharmaceutical sciences, Drug Research Academy, by Associate Professor Mingshi Yang, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen.

The DRA lecture is free of charge and open for attendance by all interested parties. It is not necessary to pre-register.