Pifusertib hydrochloride

• CAT Number: I045083
• CAS Number: 2930090-28-9
• Molecular Formula: C26H25ClN4O2
• Molecular Weight: 460.96
• Purity: ≥95%
• Synonyms: 3-amino-1-methyl-3-[4-(5-phenyl-8-oxa-3,6,12-triazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-4-yl)phenyl]cyclobutan-1-ol;hydrochloride
• InChI: InChI=1S/C26H24N4O2.ClH/c1-25(31)14-26(27,15-25)19-9-7-17(8-10-19)22-23(18-5-3-2-4-6-18)30-16-32-21-11-12-28-13-20(21)24(30)29-22;/h2-13,31H,14-16,27H2,1H3;1H
• InChIKey: JPKYUPVHSPWRNX-UHFFFAOYSA-N
• SMILES: CC1(CC(C1)(C2=CC=C(C=C2)C3=C(N4COC5=C(C4=N3)C=NC=C5)C6=CC=CC=C6)N)O.Cl

Pifusertib (TAS-117) hydrochloride is a potent, selective, orally active allosteric Akt inhibitor (with IC50s of 4.8, 1.6, and 44 nM for Akt1, 2, and 3, respectively). Pifusertib hydrochloride triggers anti-myeloma activities and enhances fatal endoplasmic reticulum (ER) stress induced by proteasome inhibition. Pifusertib hydrochloride induces apoptosis and autophagy[1].
Pifusertib (1 μM; 6 hours) blocks basal phosphorylation of Akt and downstream p-FKHR/FKHRL1 in MM cells with high baseline p-Akt[1].
Pifusertib (0-10 μM; 72 hours) selectively inhibits Akt and induces cytotoxicity in MM cells with high baseline phosphorylation of Akt[1].
Pifusertib abrogates the cytoprotective effect of the bone marrow microenvironment associated with Akt inhibition in both MM cells and BMSCs. Pifusertib enhances Carfilzomib-induced cytotoxicity and fatal ER stress in MM cells. Pifusertib (0.5, 1 μM) triggers G0/G1 arrest followed by apoptosis, associated with induction of autophagy and endoplasmic reticulum stress response[1].
Pifusertib enhances bortezomib-induced cytotoxicity, associated with increased CHOP (a fatal ER-stress marker) and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that Pifusertib augments Bortezomib-induced ER stress and apoptotic signaling[1].
Pifusertib (12-16 mg/kg; p.o.; daily for 5 days a week, 21 days) inhibits tumor growth in murine xenograft models of human MM[1].
Pifusertib enhances bortezomib-induced MM cytotoxicity in vivo[1].

Reference

[1]. Mimura N, et al. Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. Cancer Res. 2014;74(16):4458-4469.
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