Discovery of Benzodiazepinepyrimidine Scaffold Derivatives as Potent Doublecortin-Like Kinase 1 (DCLK1) Inhibitors for the Treatment of Acute Inflammatory Diseases.

Doublecortin-like Kinase 1 (DCLK1) is a microtubule-associated serine/threonine protein. It has emerged as a promising therapeutic target for various cancers. Recently, the role of DCLK1 in inflammation has also been widely confirmed. Inhibition of DCLK1 can significantly improve the symptoms of acute inflammation. Herein, we designed and synthesized a series of novel 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]-diazepin-6-one derivatives as potential DCLK1 inhibitors and identified several highly active compounds for the treatment of acute inflammation diseases. Among them, compound 12n exhibited remarkable anti-inflammatory activity, significantly alleviating symptoms of acute lung injury (ALI) and extending the survival of sepsis model mice. Overall, this work highlights the therapeutic potential of DCLK1 inhibitor in acute inflammation disease therapy and provides valuable lead compounds for further development of DCLK1 inhibitors.