AI Article Synopsis
- Combination therapy using kinase inhibitors and chemotherapeutics that target tubulin dynamics can enhance treatment effectiveness and tackle drug resistance.
- The study presents the development of a new compound, 8g, designed to simultaneously inhibit tubulin and kinases, with promising results in inhibiting cancer cell growth.
- 8g not only halted cell cycle progression at the G2/M phase but also showed significant tumor growth suppression in an in vivo leukemia model, indicating its potential as a dual-action anti-cancer agent.
Article 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.
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| http://dx.doi.org/10.1016/j.ejmech.2023.115687 | DOI Listing |
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