Design, Synthesis And Activity Evaluation Of Aromatic Series SHP2 Inhibitors

The Src homology 2 domain containing protein tyrosine phosphatase-2(SHP2) belong to protein tyrosine phosphatase family member, which plays a an important role in hormone signaling pathways regulating processes such as cell proliferation, differentiation,adhesion,migration, and apoptosis as a potential anti-tumor therapeutic targets concern. In recent years,there were some good activity and selectivity of the inhibitor against SHP2 was found.Unfortunately, such a small number of inhibitors and structural diversity rich enough, there was no one can enter the clinical and marketed. Therefore, the development of new inhibitors SHP2 still has much room for development.We fully exploit some small molecules acid structure and inter-dihydro-perimidine benzene structure structural advantages, as a basis for the design and synthesis of compound libraries of the three in order to implement the diversity of the compound and biological activity screening. The following conclusions:Based on our previous work, focus library 1 were designed and synthesized to improve2-chloro-3-(2,5-dimethyl-1H-pyrrol-1-yl) benzoate derivatives’ structure-activity relationships.All of the synthesized compounds were evaluated for their inhibitory activities against SHP2.Fortunately, compounds containing OH of 16,in addition, Meta position on the phenyl ring compound substituted 21 and Para-substituted compound 22, which displays IC50 values of4.29 μM, 1.08 μM and 4.85 μM, show good inhibitory activity against SHP2. This provides a very good idea for the study of new development SHP2 inhibitors.To explore the structural diversity of SHP2 inhibitors, we had two good activity of compound 16, 21 for the basic compound of the pyrrole ring replaced by other substituents,such as benzene, triazole and triazole series of ortho derivatization reaction, and these compounds carboxylate, whereby design compound libraries 2. All of the synthesized compounds were evaluated for their inhibitory activities against SHP2. Fortunately,compound 58, 59, 73, which displays IC50 values of 47.57 μM, 20.56 μM and 12.69 μM,show good inhibitory activity against SHP2. Moreover, compounds 58, 59 also show better inhibitory activity and selectivity against SHP2 more than SHP1, which lay a certain foundation for follow-up exploring high activity and selectivity of SHP2 inhibitors.Inspired by a class-diamino benzene PTPs inhibitors, we use some aliphatic chain or an aromatic chain with salicylic acid substitution reaction of a hydroxyl group on the basis of the two active salicylic acid-based compound 15, 20, and the pyrrole ring is replaced between2,3-dihydro-perimidine benzene group designed and synthesized focusing compound libraries3. All of the synthesized compounds were evaluated for their inhibitory activities against SHP2. Among them, Compounds 86, 87, 88, 89, 90, 91 which displayed an IC50 value of25.30μM, 21.50μM, 21.60μM, 5.00μM, 0.5μM and 1.0μM respectively, have shown a moderate inhibitory activity against SHP2. More importantly, these Compounds had great selectivity for SHP1 than for SHP2, which lay a certain foundation for follow-up exploring high activity and selectivity of SHP1 inhibitors.In short, we designed and synthesized focus library 1-3 on the basis of previous work.we summarized the structure-activity relationships(SARs) of benzoic acid and interdihydro-perimidine benzene derivatives, and obtained novel and potent inhibitors 16, 21, 22,58, 59, 73 and 86~91, which lay a certain foundation for follow-up exploring further SHP2 inhibitories.