Marine alkaloid rigidin analogues as potential selective inhibitors of SHP1, a new strategy for cancer immunotherapeutics

Abstract

SHP1 is a protein tyrosine phosphatase playing a central role in immunity, cell growth, development, and survival. The inhibition of SHP1 can help in better prognosis in various disorders like breast and ovarian cancer, melanoma, atherosclerosis, hypoxia, hypoactive immune response, and familial dysautonomia. The currently available inhibitors of SHP1 have the side effect of inhibiting the activity of SHP2, which shares >60% sequence similarity with SHP1 but has distinct biological functions. Thus, there is a need to search for novel specific inhibitors of SHP1. The current study uses a combination of virtual screening and molecular dynamic simulations, followed by PCA and MM-GBSA analysis, to screen about 35000 compounds; to predict that two rigidin analogues can potentially selectively inhibit SHP1 but not SHP2. Our studies demonstrate that these rigidin analogues are more potent at inhibiting SHP1 than the commercially available inhibitor NSC-87877. Further, cross-binding studies with SHP2 exhibited poor binding efficiency and lower stability of the complex, thus indicating a specificity of the rigidin analogues for SHP1, which is crucial in preventing side effects due to the diverse physiological functions of SHP2 in cellular signaling, proliferation, and hematopoiesis. Additionally, SHP1 is essential in mediating the inhibitory signaling in antitumor immune cells like NK and T cells. Hence, the rigidin analogues that inhibit SHP1 will potentiate the anti-tumor immune response by the release of inhibitory function of NK cells, thus driving NK activating response, in addition to their intrinsic anti-tumor function. Thus, SHP1 inhibition is a novel double-blade approach towards anti-cancer immunotherapeutics. Communicated by Ramaswamy H. Sarma