2. Academic Validation
  3. The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor

The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor

  • Bioorg Med Chem Lett. 2016 Jun 1;26(11):2580-3. doi: 10.1016/j.bmcl.2016.04.037.
Jeung Kuk Park 1,  Sunmin Kim 1,  Yu Jin Han 1,  Seong Hwan Kim 2,  Nam Sook Kang 3,  Hyuk Lee 4,  SangYoun Park 5
Affiliations

Affiliations

  • 1 School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea.
  • 2 Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 3 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 4 Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: leeh@krict.re.kr.
  • 5 School of Systems Biomedical Science, Soongsil University, Seoul 06978, Republic of Korea. Electronic address: psy@ssu.ac.kr.
PMID: 27117431 DOI: 10.1016/j.bmcl.2016.04.037
Abstract

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.

Keywords

Cancer; Drug discovery; FBDD; Inhibitor; PAK4.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117218
    PAK4抑制剂
    PAK
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