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

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

  • J Med Chem. 2025 Oct 23;68(20):21560-21576. doi: 10.1021/acs.jmedchem.5c01811.
Shanchao Wu 1 2,  Lei Wang 3,  Yingqi Song 2,  Changlu Li 2,  Xiaoyao Lu 4,  Qingwei Bu 4,  Keliang Li 1,  Yuping Chen 1,  Hua Sun 1,  Guang Liang 5,  Gaozhi Chen 4,  Chunquan Sheng 1 2
Affiliations

Affiliations

  • 1 The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
  • 2 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 3 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China.
  • 4 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 5 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China.
PMID: 41056415 DOI: 10.1021/acs.jmedchem.5c01811
Abstract

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.

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