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.
