Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor
- Cancer Lett. 2014 Jul 10;349(1):45-50. doi: 10.1016/j.canlet.2014.03.024.
- 1. Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea.
- 2. School of Systems Biomedical Science, Soongsil University, Seoul 156-743, Republic of Korea.
- 3. Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea.
- 4. Research Institute, DongWha Pharm. Co., Gyeonggi-do 446-902, Republic of Korea.
- 5. Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea. Electronic address: [email protected].
- 6. School of Systems Biomedical Science, Soongsil University, Seoul 156-743, Republic of Korea. Electronic address: [email protected].
Functional versatility and elevated expression in cancers have endowed p21-activated kinase 4 (PAK4) as one of the first-in-class anti-cancer drug target. In this study, a novel PAK4 Inhibitor, KY-04031 (N(2)-(2-(1H-indol-3-yl)ethyl)-N(4)-(1H-indazol-5-yl)-6-methoxy-1,3,5-triazine-2,4-diamine), was discovered using a high-throughput screening. Analysis of the complex crystal structure illustrated that both indole and indazole of KY-04031 are responsible for PAK4 hinge interaction. Moreover, the molecule's triazine core was found to mimic the ribose of the natural ATP substrate. The cell-based anti-cancer potency of KY-04031 was less effective than the pyrroloaminopyrazoles; however, the unique molecular feature of KY-04031 can be exploited in designing new PAK4 inhibitors.