The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor.
p21-Activated kinases (PAKs) which belong to the family of ste20 serine/threonine protein kinases regulate cytoskeletal reorganization, cell motility, cell proliferation, and oncogenic transformation which are all related to the cellular functions during cancer induction and metastasis. The fact that PAK mutations are detected in multiple tumor tissues makes PAKs a novel therapeutic drug target. In this study, an imidazo[4,5-b]pyridine-based PAK4 inhibitor, KY-04045 (6-Bromo-2-(3-isopropyl-1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridine), was discovered using a virtual site-directed fragment-based drug design and was validated using an inhibition assay. Although PAK4 affinity to KY-04045 seems much weaker than that of the reported PAK4 inhibitors, the location of KY-04045 is clearly defined in the structure of PAK4 co-crystallized with KY-04045. The crystal structure illustrates that the pyrazole and imidazopyridine rings of KY-04045 are sufficient for mediating PAK4 hinge loop interaction. Hence, we believe that KY-04045 can be exploited as a basic building block in designing novel imidazo[4,5-b]pyridine-based PAK4 inhibitors.
School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea.
Jeung Kuk
JK
Park
School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea.
Sunmin
S
Kim
School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea.
Yu Jin
YJ
Han
Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Seong Hwan
SH
Kim
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
Nam Sook
NS
Kang
Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: leeh@krict.re.kr.
Hyuk
H
Lee
School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea. Electronic address: psy@ssu.ac.kr.
SangYoun
S
Park
D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000600672:imidazo(4,5-b)pyridine; C116367:PAK4 protein, human; D054462:p21-Activated Kinases
Cancer; Drug discovery; FBDD; Inhibitor; PAK4