AT13148 is an oral, ATP-competitive, multi-AGC kinase inhibitor with IC50 of 38 nM/402 nM/50 nM, 8 nM, 3 nM, and 6 nM/4 nM for Akt1/2/3, p70S6K, PKA, and ROCKI/II, respectively. Phase 1.
Afuresertib (GSK2110183) is a potent, orally bioavailable Akt inhibitor with Ki of 0.08 nM, 2 nM, and 2.6 nM for Akt1, Akt2, and Akt3, respectively. Phase 2.
SC79 is a brain-penetrable Akt phosphorylation activator and an inhibitor of Akt-PH domain translocation.
MK-2206 2HCl is a highly selective inhibitor of Akt1/2/3 with IC50 of 8 nM/12 nM/65 nM in cell-free assays, respectively; no inhibitory activities against 250 other protein kinases observed. Phase 2.
Features:The first allosteric small molecule inhibitor of Akt to enter clinical development.
AZD5363 potently inhibits all isoforms of Akt(Akt1/Akt2/Akt3) with IC50 of 3 nM/8 nM/8 nM in cell-free assays, similar to P70S6K/PKA and lower activity towards ROCK1/2. Phase 2.
Features:Moderate preclinical tolerability, and PD characteristics of an AKT inhibitor. Distinct profile from other AKT inhibitors in clinical development.
Ipatasertib (GDC-0068) is a highly selective pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 5 nM/18 nM/8 nM in cell-free assays, 620-fold selectivity over PKA. Phase 2.
GSK690693 is a pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 2 nM/13 nM/9 nM in cell-free assays, also sensitive to the AGC kinase family: PKA, PrkX and PKC isozymes. Phase 1.
Perifosine (KRX-0401) is a novel Akt inhibitor with IC50 of 4.7 μM in MM.1S cells, targets pleckstrin homology domain of Akt. Phase 3.
A-674563 is an Akt1 inhibitor with Ki of 11 nM in cell-free assays, modest potent to PKA and >30-fold selective for Akt1 over PKC.
Features:Orally bioavailable compound (achieved by replacing indole of A-443654 with phenyl moiety) and somewhat less selective for Akt over PKA than A-443654.
Triciribine is a DNA synthesis inhibitor, also inhibits Akt in PC3 cell line and HIV-1 in CEM-SS, H9, H9IIIB, U1 cells with IC50 of 130 nM and 20 nM, respectively; does not inhibit PI3K/PDK1; 5000-fold less active in cells lacking adenosine kinase. Phase 1/2.