Design, synthesis, and biological evaluation of 3, 5-disubsituted-1H-pyrazolo[3,4-b]pyridines as multiacting inhibitors against microtubule and kinases

Chengqing Ning; Axiao Tao; Jing Xu

doi:10.1016/j.ejmech.2023.115687

Design, synthesis, and biological evaluation of 3, 5-disubsituted-1H-pyrazolo[3,4-b]pyridines as multiacting inhibitors against microtubule and kinases

Eur J Med Chem. 2023 Nov 5:259:115687. doi: 10.1016/j.ejmech.2023.115687. Epub 2023 Jul 27.

Authors

Chengqing Ning¹, Axiao Tao², Jing Xu³

Affiliations

¹ Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, 518055, China; SUSTech Academy for Advanced Interdisciplinary Studies, Shenzhen, 518055, China. Electronic address: ningcq@sustech.edu.cn.
² Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, 518055, China.
³ Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology, Shenzhen, 518055, China. Electronic address: xuj@sustech.edu.cn.

PMID: 37544183
DOI: 10.1016/j.ejmech.2023.115687

Abstract

Combination therapy of kinases inhibitors and chemotherapeutics targeting tubulin dynamics is an important strategy to improve therapeutic efficacy and overcome the resistance to single-target drug therapies. Inspired by this, we report herein the rational design of 3,5-disubsituted-1H-pyrazolo[3,4-b]pyridines as multiacting molecules that are capable of inhibiting tubulin and kinases simultaneously. Among them, 8g showed excellent antiproliferative activities toward a panel of cancer cell lines. 8g strongly inhibited tubulin assembly and demonstrated a potent inhibition toward FLT3 and Abl1 in both enzymatic and cellular assays. 8g caused a cell cycle arrest at G2/M phase, and significantly disrupted HUVEC tube formation. In vivo efficacy studies showed that 8g significantly inhibited tumor growth on the K562 leukemia xenograft model at 10 mg/kg. Collectively our studies suggest that the excellent antiproliferative potency of 8g may be attributed to its potent inhibitory activity against both microtubule and kinases.

Keywords: ABL1; FLT3; kinase; multitarget; tubulin.

MeSH terms

Antineoplastic Agents*
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Microtubules / metabolism
Pyridines
Structure-Activity Relationship
Tubulin Modulators / pharmacology
Tubulin* / metabolism

Substances

Tubulin
Tubulin Modulators
Pyridines
Antineoplastic Agents