Background: Specifically blocking HSP90-CDC37 interaction is emerging as a prospective strategy for cancer therapy. Aim: Applying a kinase pseudopeptide rationale to the discovery of HSP90-CDC37 protein-protein interaction (PPI) inhibitors. Methods: Pseudosubstrates were identified through sequence alignment and evaluated by biolayer interferometry assay, co-immunoprecipitation assay and antiproliferation assay. Results: TAT-DDO-59120 was identified to disrupt HSP90-CDC37 PPI through directly binding to HSP90, both extracellularly and intracellularly. In addition, the identified peptide showed ideal antiproliferative activity against the colorectal cancer cell HCT116 (IC50 = 12.82 μM). Conclusion: Compared with the traditional method of screening a large compound library to identify PPI inhibitors, this method is rapid and efficient with strong purpose, which provides a novel strategy for designing HSP90-CDC37 PPI inhibitors.
Keywords: HSP90–CDC37 PPI inhibitor; pseudosubstrate; rational design; sequence alignment.