Ipatasertib (GDC-0068)

Selective Akt Inhibitor

CCT128930 : Akt2-selective, IC50=6 nM.

Most Potent Akt Inhibitor

AZD5363 : Akt1, IC50=3 nM; Akt2, IC50=8 nM; Akt3, IC50=8 nM.

Akt Inhibitor in Clinical Trial

Perifosine (KRX-0401) : Phase III for relapsed and refractory multiple myeloma.

Newest Akt Inhibitor

AZD5363 : Potent inhibitor of all isoforms of Akt (Akt1/Akt2/Akt3) with IC50 of 3 nM/8 nM/8 nM, similar to P70S6K/PKA and lower activity towards ROCK1/2.

Afuresertib (GSK2110183) ^New

Afuresertib (GSK2110183) is a potent, orally bioavailable Akt inhibitor with K_i of 0.08 nM, 2 nM, and 2.6 nM for Akt1, Akt2, and Akt3, respectively. Phase 2.

AT13148 ^New

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.

SC79 ^New

SC79 is a brain-penetrable Akt phosphorylation activator and an inhibitor of Akt-PH domain translocation.

MK-2206 2HCl

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. MK-2206 2HCl induces autophagy and apoptosis in cancer cells. Phase 2.

Features:The first allosteric small molecule inhibitor of Akt to enter clinical development.

Capivasertib (AZD5363)

Capivasertib (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.

GSK690693

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. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family with IC50 of 50 nM and 81 nM, respectively. GSK690693 affects Unc-51-like autophagy activating kinase 1 (ULK1) activity, robustly inhibits STING-dependent IRF3 activation. Phase 1.

Perifosine (KRX-0401)

Perifosine (KRX-0401, NSC639966) 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

A-674563 is an Akt1 inhibitor with K_i 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

Triciribine (NSC 154020, VD-0002, vqd-002, API-2) 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.

Honokiol

Honokiol is the active principle of magnolia extract that inhibits Akt-phosphorylation and promotes ERK1/2 phosphorylation. Honokiol causes G0/G1 phase arrest, induces apoptosis, and autophagy via the ROS/ERK1/2 signaling pathway. Honokiol inhibits hepatitis C virus (HCV) infection. Phase 3.