首页|Design,synthesis and evaluation of the first DYRK1A degrader for promoting the proliferation of pancreatic β-cells
Design,synthesis and evaluation of the first DYRK1A degrader for promoting the proliferation of pancreatic β-cells
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Dual-specificity tyrosine-phosphorylation-regulated kinase 1A(DYRK1A)is the most promising target for diabetes treatment by promoting β-cell proliferation.The desmethylbellidifolin(DMB)as a DYRK1A in-hibitor could facilitate β-cell proliferation in vivo and in vitro.However,DMB has the problem of weak binding affinity to DYRK1A,which means that continuous high concentration administration of DMB is effective for the diabetes.In order to solve this problem,we designed and synthesized a series of DMB-based proteolysis targeting chimeras(PROTACs)by taking advantage of the property of PROTAC that in-duce protein degradation in a cycle-catalytic manner.MDM2-based PROTAC X1-4P-MDM2 was identified as the most active PROTAC molecule.Mechanism research showed that X1-4P-MDM2 formed a ternary complex with DYRK1A and murine double minute 2(MDM2),and induced the degradation of DYRK1A through the ubiquitin-proteasome system pathway.At a dose much lower than that of DMB,X1-4P-MDM2 still significantly enhanced β-cell proliferation by inhibiting transforming growth factor beta(TGF-β)and promoting the mitogen-activated protein kinases/extracellular signal-regulated kinase(MAPK/ERK)signaling pathway,which may provide a new strategy for the application of DMB in diabetes.
Fujian Key Laboratory of Chinese Materia Medica,Institute of Structural Pharmacology & TCM Chemical Biology,College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China
Wuya College of Innovation,Key Laboratory of Structure-Based Drug Design & Discovery,Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China
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