Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor.
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.
Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea.
Byung Jun
BJ
Ryu
School of Systems Biomedical Science, Soongsil University, Seoul 156-743, Republic of Korea.
Sunmin
S
Kim
Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea.
Bora
B
Min
School of Systems Biomedical Science, Soongsil University, Seoul 156-743, Republic of Korea.
Keon Young
KY
Kim
Research Institute, DongWha Pharm. Co., Gyeonggi-do 446-902, Republic of Korea.
Jin Soo
JS
Lee
Research Institute, DongWha Pharm. Co., Gyeonggi-do 446-902, Republic of Korea.
Whui Jung
WJ
Park
Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea.
Hyuk
H
Lee
Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Yuseong-Gu, Daejeon 305-600, Republic of Korea. Electronic address: hwan@krict.re.kr.
Seong Hwan
SH
Kim
School of Systems Biomedical Science, Soongsil University, Seoul 156-743, Republic of Korea. Electronic address: psy@ssu.ac.kr.
SangYoun
S
Park
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C116367:PAK4 protein, human; D054462:p21-Activated Kinases
Cancer; Drug discovery; HTS; PAK4; Protein kinase; X-ray crystallography