Ipatasertib dihydrochloride 是ATP竞争性的pan-Akt选择性抑制剂，抑制Akt1，Akt2，Akt3，IC50分别为 5，18，8 nM。

Ipatasertib dihydrochloride is a highly selective and ATP-competitive inhibitor of pan-Akt (IC50s: 5, 18 and 8 nM for Akt1, Akt2 and Akt3, respectively).

Ipatasertib displays more than 600 and more than 100-fold selectivity for Akt1 in IC50 against the closely related kinases PKA and p70S6K, respectively. Ipatasertib inhibits only 3 other kinases by more than 70% at 1 μM concentration (PRKG1α, PRKG1β, and p70S6K) when tested at 1 μM in a panel of 230 protein kinases, which includes 36 human AGC family members. IC50s measured for these 3 kinases are 98, 69, and 860 nM, respectively. The relationship between pharmacokinetics (PK) and pharmacodynamics (PD) of Ipatasertib is investigated in 3 xenograft models that showed a dose-dependent response to drug treatment: MCF7-neo/HER2, TOV-21G.x1, and LNCaP. The mean cell viability IC50 of Ipatasertib in these 3 cell lines is 2.56, 0.44, and 0.11 μM, respectively. Ipatasertib shows a more than 100-fold selectivity for Akt1 over the next most potently inhibited non-Akt kinase, p70S6K, in the screening kinase panel with the exception of PKG1 (relative to which Ipatasertib is >10-fold more selective for Akt1) [2].

Ipatasertib is typically efficacious in xenograft models in which Akt is activated because of genetic alterations including PTEN loss, PIK3CA mutations/amplification, or HER2 overexpression. The combination of Ipatasertib with RP-56976 or NSC 241240 is tolerated with less than 5% body weight loss when compared with treatment with each chemotherapeutic agent alone. The daily dosing of Ipatasertib in combination with RP-56976 induces tumor regression and stasis in the PC-3 and MCF7-neo/HER2 xenograft models, at doses where every single agent is ineffective or only causes modest tumor growth delay, when tested in vivo. Similarly, enhanced TGI is observed in the OVCAR3 ovarian cancer xenograft model when Ipatasertib is combined with NSC 241240 [2].

1396257-94-5

C24H34Cl3N5O2

530.92

GDC-0068 dihydrochloride;RG-7440 dihydrochloride

DMSO:125 mg/mL (235.44 mM),Need ultrasonic
H2O:41 mg/mL (77.22 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years