Design, synthesis and biological evaluation of 2-H pyrazole derivatives containing morpholine moieties as highly potent small molecule inhibitors of APC-Asef interaction.


State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, PR China. Electronic address: [Email]


Mutated adenomatous polyposis coli (APC) selectively combining with Asef has been reported to be implicated in promoting colon cancer proliferation, invasion and metastasis in several cancer biotherapy studies. However, there were universally resistance and harsh terms in disrupting APC-Asef interaction in biotherapy. Under the circumstances small-molecule inhibitors as the new APC interface could resolve the problems. In this research, a series of novel dihydropyrazole derivatives containing morpholine as high potent interaction inhibitors between APC and Asef were first synthesized after selection by means of docking simulation and virtual screening. Afterwards they were evaluated interaction inhibition of APC-Asef and pharmacological efficiency both in vitro and in vivo utilizing orthotopic transplantation model with multi-angle of view. Among them, compound 7g exhibited most excellent anti-proliferation activities against HCT116 cells with IC50 of 0.10 ± 0.01 μM than Regorafenib (IC50 = 0.16 ± 0.04 μM). The results favored our rational design intention and provides a new class of small-molecule inhibitors available for the development of colon tumor therapeutics targeting APC-Asef interaction inhibitions.


APC,Asef,Colorectal cancer,Docking simulation,Orthotopic transplantation model,Small-molecule inhibitors,

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