TNO155 is an orally bioavailable allosteric inhibitor of Src homology region 2 domain-containing phosphatase 2 (SHP-2; IC50 = 0.011 ?M).1 It is selective for SHP-2 over a panel of 52 kinases and phosphatases (IC50s = >10 ?M for all). TNO155 decreases phosphorylation of ERK in, and inhibits proliferation of, KYSE-520 human esophageal cancer cells (IC50s = 0.011 and 0.1 ?M, respectively). It acts synergistically with dabrafenib and trametinib to inhibit proliferation of B-RAFV600E-expressing HT-29, RKO, and MDST8 colorectal cancer cells.2 TNO155 (2.5, 10, and 20 mg/kg twice per day) reduces tumor growth in a KYSE-520 mouse xenograft model.1
1.LaMarche, M.J., Acker, M., Argintaru, A., et al.Identification of TNO155, an allosteric SHP2 inhibitor for the treatment of cancerJ. Med. Chem.63(22)13578-13594(2020) 2.Liu, C., Lu, H., Wang, H., et al.Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signalingClin. Cancer Res.27(1)342-354(2021)