Design, Synthesis And Activity Evaluation Of SHP2 Inhibitors Containing Oxadiazole Structural Units

Protein tyrosine phosphatases（PTPs）and protein tyrosine kinases（PTKs）work synergistically on many cell activities,including proliferation,differentiation,survival,metabolism and immune response.At present,a variety of small molecule inhibitors targeting PTKs have been approved for marketing by the FDA,and many small molecule inhibitors are in the clinical stage.However,as the PTPs family protein,which is most closely related to the PTKs family and acts synergistically,no targeted inhibitors have been successfully approved by the FDA.SHP2 in the PTPs family is encoded by PTPN11,is widely expressed in various human organs,and participates in multiple intracellular carcinogenic signal transduction cascades.Studies have shown that SHP2 abnormalities（including identified mutations,overexpression and down-regulation）have been found in several human diseases,which can cause changes in the catalytic activity and binding affinity of the substrate and the binding partner.The disorder of SHP2 can cause various human diseases,including Noonan syndrome（NS）,Leopard syndrome（LS）,leukemia and solid tumors.There are no effective clinical treatments for the treatment of hematological diseases,especially for rare diseases such as juvenile myeloid leukemia（JMML）and acute myeloid leukemia（AML）.It has been confirmed that SHP2 in leukemia can be used as a tumor promoter.In the past two decades,small molecule SHP2 inhibitors have attracted widespread attention.However,the high homology of the catalytic domains of the PTPs family presents huge challenges.At the same time,the need to improve the cell permeability and bioavailability of small molecule inhibitors hinders the development and application of SHP2 inhibitors.Therefore,there is an urgent need to develop small molecule inhibitors with high SHP2 selectivity,novel structure,and high selectivity.Oxadiazole as an ester bond and an amide bond biological electron is a pharmaceutical bracket that has received interest,has been widely used in pharmaceutical molecular design studies.There is currently extensive biological activity,which has important application value.However,there is not currently oxadiazole compound that is targeted to inhibit SHP2.Therefore,this paper applies oxadiazole heterocyclic to the design of small molecule SHP2 inhibitors,and combines it and biologically active evaluation.In the early stage of our research group,we designed and synthesized multiple compound libraries targeting the PTPs family based on positive compounds containing 2,3-dihydroperimidine structural units.This paper is always based on the existing structural effects.A series of oxadiazole compounds can be obtained through skeleton transition.Firstly,1,2,4-oxadiazole is used as the core,and the structure is designed and synthesized by replacing various heterocycles and introducing different substituents at the 3-position benzene ring of 1,2,4-oxadiazole.A series of 1,2,4-oxadiazole derivatives were obtained.SHP2 protein inhibitory biological activity evaluation experiments show that when the linking group is nitrobenzene,compound 10 is obtained,which shows a certain inhibitory activity against SHP2protein(IC₅₀=10.44±0.37μM).Then we further designed and synthesized a series of substituted compounds with nitro groups.Among them,we found compound 19(IC₅₀=7.94±0.71μM).We further derivatized and obtained compound 35(IC₅₀=42.12±3.11μM)and compound 37(IC₅₀=9.94±0.17μM).According to the inhibitory activity of 1,2,4-oxadiazole,designed and synthesized a series of 1,3,4-oxadiazole compounds.Obtained compound 63(IC₅₀=8.00±0.85μM),compound 66(IC₅₀=2.73±0.20μM),compound 68(IC₅₀=11.35±0.68μM),compound 70(IC₅₀=12.92±1.23μM)and compound 77(IC₅₀=24.60±0.40μM).Summary 1,2,4-oxazole compound and 1,3,4-oxazole compound on SHP2protein inhibitory activity evaluation results,found that 4-methyl-3-nitrophenyl and 3-（furan-2-formamide）-phenyl groups were important to effectively effect.Further cell experiments show that compound 66 has good anti-proliferation ability in TF-1 cells(IC₅₀=6.67±0.58μM)and down-regulate the p-ERK signaling pathway in TF-1 cells.This research provides new ideas for the subsequent development of new SHP2 protein inhibitors.