2. Academic Validation
  3. Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor

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.
Byung Jun Ryu 1,  Sunmin Kim 2,  Bora Min 3,  Keon Young Kim 2,  Jin Soo Lee 4,  Whui Jung Park 4,  Hyuk Lee 3,  Seong Hwan Kim 5,  SangYoun Park 6
Affiliations

Affiliations

  • 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: hwan@krict.re.kr.
  • 6 School of Systems Biomedical Science, Soongsil University, Seoul 156-743, Republic of Korea. Electronic address: psy@ssu.ac.kr.
PMID: 24704155 DOI: 10.1016/j.canlet.2014.03.024
Abstract

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.

Keywords

Cancer; Drug discovery; HTS; PAK4; Protein kinase; X-ray crystallography.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124764
    PAK4 Inhibitor
    PAK