Design,Synthesis And Activity Of Protein Tyrosine Phosphatase SHP-2 Inhibitor

Modification of proteins through reversible phosphorylation is the most ubiquitously regulated aspect of cell signaling.This regulation is precisely performed by protein tyrosine kinases(PTK)and protein tyrosine phosphatases(PTP).The PTPs function as tumor suppressors in some systems and have been shown to play roles in cell cycle regulation as well as T-cell activation.PTPs are generally considered to be the negative regulators of PTKs.However,among the PTPs,protein tyrosine phosphatase 2(SHP-2)is unique in that it binds and dephosphorylates RAS,and thus increases RAS-RAF binding and activates downstream proliferative RAS/ERK/MAPK signaling.SHP-2 has long been proposed as a cancer drug target.Several small molecule compounds with different mechanisms of SHP-2 inhibition have been reported,but none are commercially available.In the past 10 years,many SHP-2 inhibitors have been identified as natural compounds or synthesized.Some of them exhibit good inhibitory activity and selectivity over other PTPs,such as PTP1 B.However,few SHP-2 inhibitors have been investigated in clinical studies,and no SHP-2 inhibitor has become a registered drug.The main problems have been a lack of cellular activity and selectivity.The structure of SHP-2 is similar to those of other classical non-receptor tyrosine-specific phosphatases.The research work of this thesis is to design SHP-2 inhibitors using computer-aided drug molecular design simulation and virtual screening software to synthesize the designed compounds by chemical synthesis.A total of two batches of molecules were designed.The first batch was 12 small molecule compounds bound to acid chloride,followed by in vitro activity screening at the molecular level.The second batch was 12 small molecule compounds bound to chlorosulfonium.None of the 24 small molecules with chlorohydrazone as a heterocycle had inhibitory activity against SHP-2.For the structure of SHP-2,I propose from four directions Improvement.Hope to provide suggestions for the development of SHP-2 inhibitors.