Synthesis of novel 1H-Pyrazolo[3,4-b]pyridine derivatives as DYRK 1A/1B inhibitors

Areum Park; Jieon Hwang; Joo-Youn Lee; Eun Ji Heo; Yoon-Ju Na; Sein Kang; Kyu-Sung Jeong; Ki Young Kim; Sang Joon Shin; Hyuk Lee

doi:10.1016/j.bmcl.2021.128226

Synthesis of novel 1H-Pyrazolo[3,4-b]pyridine derivatives as DYRK 1A/1B inhibitors

Bioorg Med Chem Lett. 2021 Sep 1:47:128226. doi: 10.1016/j.bmcl.2021.128226. Epub 2021 Jun 26.

Authors

Areum Park¹, Jieon Hwang², Joo-Youn Lee³, Eun Ji Heo⁴, Yoon-Ju Na⁵, Sein Kang⁵, Kyu-Sung Jeong⁶, Ki Young Kim⁷, Sang Joon Shin⁸, Hyuk Lee⁹

Affiliations

¹ Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.
² Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
³ Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
⁴ Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
⁵ Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea; Drug Discovery Platform Technology Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
⁶ Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.
⁷ Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea; Drug Discovery Platform Technology Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: kykim@krict.re.kr.
⁸ Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address: ssj338@yuhs.ac.
⁹ Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: leeh@krict.re.kr.

PMID: 34182093
DOI: 10.1016/j.bmcl.2021.128226

Abstract

As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8 and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC₅₀ Values of 3-287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory enzymatic activity (IC₅₀ = 3 nM) and cell proliferation inhibitory activity (IC₅₀ = 1.6 µM) towards HCT116 colon cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic interactions.

Keywords: Colon cancer; DYRK1A; DYRK1B; Kinase Inhibitors; Organoid; Pyrazolopyridines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Dyrk Kinases
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

1H-pyrazolo(3,4-b)pyridine
Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases