Battling Drug Resistance of Tumors using novel SHP2 Inhibitors

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The non-receptor tyrosine phosphatase SHP2 (encoded by PTPN11) has been implicated in signaling of tyrosine kinase receptors, and to induce physiological and pathophysiological processes in cells. Recent genetic analyses in mice showed that SHP2 functions in the development and maintenance of various organs. In humans, germline and somatic mutations of PTPN11 are associated with Noonan and Leopard syndromes, as well as with a number of malignancies. SHP2 is upregulated in 70% of invasive breast cancers, and shRNA interference inhibited tumor growth and cancer stem cells in xenograft models. Therefore, SHP2 is an attractive target in cancer therapy.And so, the identification of small molecule SHP2 inhibitors is in great demand for therapeutic purposes. However, no SHP2 inhibitor has yet reached advanced stages of clinical trials. Our laboratories have identified and characterized the active site SHP2 inhibitor GS493. We have shown that GS493 in combination with MEK inhibitors can block the growth of endogenous KRAS-mutant tumors in mice and prevent RTK-mediated resistance to BRAF inhibitor vemurafenib in BRAF-mutant colon cancer and melanoma cells. Recently, others have developed new inhibitors of SHP2 that act by an allosteric mechanism, and keep SHP2 in a closed, auto-inhibitory conformation. However, accumulating evidence suggests that compared to active site inhibitors, depending on the mutational and activation state, the allosteric inhibitors are less efficacious. Nearly half of patients with SHP2-mutated cancers bear strongly activating mutations and successful suppression of SHP2 activity in these mutated tumors may be difficult to achieve with allosteric inhibitors in clinical settings. In subsequent chemical optimization studies, we plan to improve the structural features of our scaffold and convert it into a drug-like lead molecule. We will (i) develop and characterize novel highly active, selective, cell-permeable and metabolically stable inhibitors of SHP2 by medicinal chemistry approaches and biochemical studies, (ii) design potent irreversible SHP2 inhibitors that exert a prolonged residence time and withstand strongly activating mutations of SHP2, (iii) analyze the effect of acute perturbation of SHP2 in cancer cell lines, patient-derived organoids and mouse models, and to mechanistically dissect the role of reversible and irreversible active site inhibition in combination with MEK inhibition on the drug resistance of KRAS-mutant tumors, (iv) analyze the synergistic effect of combined active site and allosteric inhibition of SHP2 in preventing drug resistance of tumors, and finally, (v) establish the combined catalytic and allosteric site inhibition of SHP2 as a new therapeutic approach to treat KRAS-driven tumors. These studies will yield novel insights into the cellular role of SHP2 in mediating drug resistance in cancer and have a high potential of being translated into the development of novel therapies in oncology.