tcsc0975 Ipatasertib

Ipatasertib (GDC-0068) is a highly selective and ATP-competitive pan-Akt inhibitor with IC₅₀s of 5, 18 and 8 nM for Akt1, Akt2 and Akt3, respectively.

IC50 & Target: IC50: 5±7 nM (Akt1), 18±10 nM (Akt2), 8±9 nM (Akt3), 3100±705 nM (PKA)^[1]

In Vitro: Ipatasertib (GDC-0068) shows more than 600 and more than 100-fold selectivity for Akt1 in IC₅₀ against the closely related kinases PKA and p70S6K, respectively. When tested at 1 μM in a panel of 230 protein kinases, which includes 36 human AGC family members, GDC-0068 inhibits only 3 other kinases by more than 70% at 1 μM concentration (PRKG1α, PRKG1β, and p70S6K). IC₅₀s measured for these 3 kinases are 98, 69, and 860 nM, respectively. Thus, with the exception of PKG1 (relative to which Ipatasertib (GDC-0068) is >10-fold more selective for Akt1), Ipatasertib (GDC-0068) displays a more than 100-fold selectivity for Akt1 over the next most potently inhibited non-Akt kinase, p70S6K, in the screening kinase panel. The relationship between pharmacokinetics (PK) and pharmacodynamics (PD) of Ipatasertib (GDC-0068) is investigated in 3 xenograft models that showed dose-dependent response to drug treatment: MCF7-neo/HER2, TOV-21G.x1, and LNCaP. The mean cell viability IC₅₀ of GDC-0068 in these 3 cell lines is 2.56, 0.44, and 0.11 μM, respectively^[2].

In Vivo: Ipatasertib (GDC-0068) is typically efficacious in xenograft models in which Akt is activated because of genetic alterations including PTEN loss, PIK3CA mutations/amplifications, or HER2 overexpression. In these models, tumor growth delay, stasis, or regression is achieved at or below 100 mg/kg daily oral dose, which is the maximum dose tested in immunocompromised mice that is well tolerated. When tested in vivo, daily dosing of Ipatasertib (GDC-0068) in combination with Docetaxel induces tumor regression and stasis in the PC-3 and MCF7-neo/HER2 xenograft models, at doses where each single agent is ineffective or only causes modest tumor growth delay. Similarly, increased TGI is observed in the OVCAR3 ovarian cancer xenograft model when Ipatasertib (GDC-0068) is combined with Carboplatin. The combination of Ipatasertib (GDC-0068) with Docetaxel or Carboplatin is tolerated with less than 5% body weight loss when compared with treatment with each chemotherapeutic agent alone^[2].