allosteric akt

Hematein inhibits Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway, and increases apoptosis in lung cancer cells. Hematein is an oxidation product of hematoxylin acted as a dye and it also is an allosteric casein kinase II inhibitor (IC50: 0.74 μM).

AKT-IN-24 (Compound M17) is an allosteric inhibitor of AKT exhibiting antitumor activity. In combination with Trametinib, it targets the AKT mTOR and MEK ERK signaling pathways while inhibiting epithelial-mesenchymal transition, resulting in a synergistic suppression effect on TNBC. This combination promotes apoptosis and inhibits cell proliferation and migration.

UNC10013 is an allosteric modulator of SETDB1, exhibiting negative allosteric regulation through covalent bond formation with Cys385 on the 3TD domain. It has a kinact/KI value of 1.0 × 10^6 M^-1*s^-1. UNC10013 effectively disrupts SETDB1-mediated Akt methylation, holding potential for application in cancer and neurodegenerative disease research.

Miransertib hydrochloride (ARQ-092 hydrochloride) is a potent, orally bioavailable, selective, and allosteric inhibitor of Akt with an IC50 of 2.7 nM, 14 nM, and 8.1 nM against Akt1, Akt2, and Akt3, respectively. It also shows significant potency against the AKT1-E17K mutant protein and holds promise for research on PI3K/AKT-driven tumors and Proteus syndrome. Additionally, Miransertib hydrochloride exhibits efficacy against Leishmania [1, 2].

Miransertib (ARQ-092) is an orally bioavailable, selective, and potent allosteric Akt inhibitor.

2-Amino-5-bromo-6-chloropyrazine is a heterocyclic building block.1,2It has been used in the synthesis of Akt inhibitors. 1.Kettle, J.G., Brown, S., Crafter, C., et al.Diverse heterocyclic scaffolds as allosteric inhibitors of AKTJ. Med. Chem.55(3)1261-1273(2012) 2.Goel, R., Luxami, V., and Paul, K.Recent advances in development of imidazo[1,2-a]pyrazines: Synthesis, reactivity and their biological applicationsOrg. Biomol. Chem.13(12)3525-3555(2015)

AKT-IN-1 (AZD-26) is an allosteric AKT inhibitor (IC50: 1.04 μM).

SHP2-IN-8 is a reversible, noncompetitive, selective and efficient allosteric SHP2 inhibitor (IC50=23 nM, Ki=22 nM), which also has effects in cells. SHP2-IN-8 can cause significant thermal displacement( Δ Tm = 7.01 ℃). SHP2-IN-8 can inhibit the phosphorylation of AKT and induce apoptosis of Hela cells.

TAS-117 hydrochloride is a selective, potent, orally active allosteric Akt inhibitor, acting on Akt1 (IC50: 4.8 nM), Akt2 (IC50: 1.6 nM) and Akt3 (IC50: 44 nM). TAS-117 hydrochloride stimulates anti-myeloma activity, enhances lethal endoplasmic reticulum stress induced by proteasome inhibition, and can induce apoptosis and autophagy.

JBJ-09-063 is a mutant-selective allosteric inhibitor of the epidermal growth factor receptor (EGFR), with potent inhibitory activity demonstrated by half-maximal inhibitory concentrations (IC50s) of 0.147 nM for EGFR L858R, 0.063 nM for EGFR L858R T790M, 0.083 nM for EGFR L858R T790M C797S, and 0.396 nM for EGFR L747S. This compound effectively decreases phosphorylation of EGFR, Akt, and ERK1 2, showing efficacy in both EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant models. JBJ-09-063 holds potential for research into EGFR-mutant lung cancer.

KAL-21404358 is a Novel allosteric inhibitor of K-RasG12D, binding to the P110 site of K-RasG12D, impairing the K-RasG12D interaction with B-Raf, and disrupting the RAF-MEK-ERK and the PI3K-AKT signaling pathway.

JBJ-09-063 TFA is a mutant-selective allosteric EGFR inhibitor with IC50 values of 0.147 nM for EGFR L858R, 0.063 nM for EGFR L858R T790M, 0.083 nM for EGFR L858R T790M C797S, and 0.396 nM for EGFR L747S mutations. It effectively reduces phosphorylation of EGFR, Akt, and ERK1 2, demonstrating efficacy in models both sensitive and resistant to EGFR tyrosine kinase inhibitors (TKI). JBJ-09-063 TFA holds potential for research in EGFR-mutant lung cancer [1].

YF704 (compound 4w), a selective allosteric inhibitor of SHP2, exhibits antiproliferative effects and induces apoptosis in cancer cells with an IC50 of 0.25 μM. Furthermore, it downregulates Erk1 2 and Akt phosphorylation levels in cancer cells [1].

MK-2206 free base is a potent, selective, and orally administered allosteric Akt inhibitor with IC50 values of 8, 12, and 65 nM for Akt1, Akt2, and Akt3, respectively. It demonstrates sensitivity in various breast cancer cell lines, including those with PIK3CA mutations and PTEN loss, indicating its potential for anticancer activities [1] [2].

Borussertib is a first-in-class covalent-allosteric inhibitor of protein kinase Akt, with an IC50 of 0.8 nM and a Ki of 2.2 nM for Aktwt.

AKT-IN-22 (compound 0R4) serves as a potent allosteric inhibitor of AKT, exhibiting anticancer properties [1].