2. Academic Validation
  3. Design, synthesis of new 3H-imidazo[4,5-b]pyridine derivatives and evaluation of their inhibitory properties as mixed lineage kinase 3 inhibitors

Design, synthesis of new 3H-imidazo[4,5-b]pyridine derivatives and evaluation of their inhibitory properties as mixed lineage kinase 3 inhibitors

  • Bioorg Med Chem Lett. 2024 Feb 10:101:129652. doi: 10.1016/j.bmcl.2024.129652.
Hye Ree Yoon 1,  Anand Balupuri 1,  Jinwoo Lee 1,  Chaeeun Lee 1,  Dong-Hyun Son 1,  Re Gin Jeoung 1,  Kyung Ah Kim 1,  Sungwook Choi 2,  Nam Sook Kang 3
Affiliations

Affiliations

  • 1 Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea.
  • 2 Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea. Electronic address: [email protected].
  • 3 Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea. Electronic address: [email protected].
PMID: 38346577 DOI: 10.1016/j.bmcl.2024.129652
Abstract

Mixed-lineage protein kinase 3 (MLK3) is implicated in several human cancers and neurodegenerative diseases. A series of 3H-imidazo[4,5-b]pyridine derivatives were designed, synthesized and evaluated as novel MLK3 inhibitors. A homology model of MLK3 was developed and all designed compounds were docked to assess their binding pattern and affinity toward the MLK3 active site. Based on this knowledge, we synthesized and experimentally evaluated the designed compounds. Majority of the compounds showed significant inhibition of MLK3 in the enzymatic assay. In particular, compounds 9a, 9e, 9j, 9 k, 12b and 12d exhibited IC50 values of 6, 6, 8, 11, 14 and 14 nM, respectively. Furthermore, compounds 9a, 9e, 9 k and 12b exhibited favorable physicochemical properties among these compounds.

Keywords

Azabenzimidazole derivatives; Homology modeling; MLK3 inhibitor; Molecular docking.

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