Experimental evidence suggests that Pin1 inhibition by API-1 up-regulates miRNA biogenesis by retaining active XPO5 conformation and suppresses HCC development, revealing the mechanism of Pin1-mediated miRNA biogenesis and unequivocally supporting API-1 as a drug candidate for HCC therapy, especially for Pin1-overexpressing, extracellular signal-regulated kinase-activated HCC. (Hepatology 2018).
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. Nowadays, pharmacological therapy for HCC is in urgent needs. Paclitaxel is an effective drug against diverse solid tumors, but commonly resisted in HCC patients. We recently have disclosed that microtubule affinity-regulating kinase 4 (MARK4) increases the microtubule dynamics and confers paclitaxel resistance in HCC, suggesting MARK4 as an attractive target to overcome paclitaxel resistance. Herein, we synthesized and identified coumarin derivatives
50
as a novel MARK4 inhibitor. Biological evaluation indicated compound
50
directly interacted with MARK4 and inhibited its activity
in vitro
, suppressed cell viability and induced apoptosis of HCC cells in a MARK4-dependent manner. Importantly, compound
50
significantly increased the drug response of paclitaxel treatment to HCC cells, providing a promise strategy to HCC treatment and broadening the application of paclitaxel in cancer therapy.
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