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

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.