| GSK690693 is a novel ATP competitive, pan-AKT kinase inhibitor. The Ki of GSK690693 is 1, 4 and 13 nM against AKT1, AKT2 and AKT3, respectively. The IC50 of GSK690693 is 2, 13, and 9 nM against AKT1, AKT 2, and AKT 3, respectively. [1] GSK690693 inhibits acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, and Burkitt lymphoma by 89%, 73%, and 67%, respectively. GSK690693 inhibits proliferation of KARPAS-231, CCRFSB, SUP B15 with EC50 of 41, 155 and 197 nM, respectively. [2] Treatment with GSK690693 results in a decrease in the abundance of phosphorylated AKT substrates, pGSK3a/b (S9/21), pFKHR/FKHRL1 (T24/32), pmTOR (S2448), pBAD (S112), and pPRAS40 (T246) in BT474, T47D, MDA-MB-468, and MDA-MB-453 cells.[3] GSK690693 effectively inhibits GSK3β (glycogen synthase kinase 3β) phosphorylation in BT474 xenografts in a dose dependent fashion when analyzed 4 hours following ip dosing in SCID (severe combined immunodeficiency) mice. GSK690693 significantly decreases GSK3β phosphorylation in BT474 tumor for up to 8 hours after single i.p. dose in SCID mice at 20 mg/kg. Furthermore, daily dosing of GSK690693 (i.p., 30 mg/kg) results in 64% inhibition of tumor growth compared to vehicle treated mice in BT474 xenografts. [1] GSK690693 is most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. GSK690693 delays tumor development and reduces the size of tumors in Lck-MyrAkt2 transgenic mice. Nearly 50% of the GSK690693-treated mice have normal thymic histology, whereas 90% of the placebo-treated mice develop thymic lymphomas or hyperplasia. [4] |
