High-throughput screening protocol created to discover SHP2 inhibitors

A team of researchers has developed a new multifunctional cross-validation high-throughput screening protocol to enable the discovery of inhibitors for the protein tyrosine phosphatase Src homology phosphotyrosyl phosphatase 2 (SHP2). The study was conducted at Zhengzhou University, China. 

According to the researchers, SHP2 is implicated in various cancers and targeting the protein has become a promising therapeutic approach.

To develop their robust cross-validation high-throughput screening protocol, the team combined a fluorescence-based enzyme assay and a conformation-dependent thermal shift assay for the discovery of SHP2 inhibitors. The researchers say this established method can effectively exclude false positive SHP2 inhibitors with fluorescence interference. 

The new technique was successfully employed to identify new protein tyrosine phosphatase domain of SHP2 (SHP2-PTP) and allosteric inhibitors. The team highlight that this protocol showed potential for identifying SHP2 inhibitors against cancer-associated SHP2 mutation SHP2-E76A. After initial screening of an in-house compound library (approximately 2300 compounds), they identified four new SHP2-PTP inhibitors and 28 novel allosteric SHP2 inhibitors, of which SYK-85 and WS-635 effectively inhibited SHP2-PTP. They also say that TK-147, an allosteric inhibitor, inhibited SHP2 potently. In structure, TK-147 could be regarded as a bioisostere of the well characterised SHP2 inhibitor SHP-099, highlighting the essential structural elements for allosteric inhibition of SHP2.

The researchers say that this process therefore represents a novel scaffold for designing new SHP2-PTP inhibitors. 

“The principle underlying the cross-validation protocol is potentially feasible to identify allosteric inhibitors or those inactivating mutants of other proteins,” the authors of the study write. “We believe that SYK-85, WS-635, and TK-147 could be used as templates for designing new SHP2-PTP and allosteric SHP2 inhibitors, respectively. Further structural modifications are undergoing in our lab and will be reported in due course.”

The results from the study are published in Acta Pharmaceutica Sinica B.