GSK690693

GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Intraperitoneal administration of GSK690693 in uncompromised mice resulted in the inhibition of GSK3b and repeated dosing of 25 in BT474 breast carcinoma xenograft mice produced a significant delay in tumor growth. GSK690693 inhibited cell growth in vitro with IC(50) values between 6.5 nM and >10µM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity.