XL147

XL147 (SAR245408) is a novel small molecule PI3K inhibitor. Activation of the PI3 kinase pathway occurs frequently in many cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. XL147 demonstrated cytotoxic activity, with a median relative IC(50) value of 10.9 µM (range 2.7-24.5 µM) in vitro. Also XL147 was well tolerated in vivo, all 44 tested xenograft models were evaluable for efficacy. XL147 (SAR245408) induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6 in HER2(+) cells. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts.