Molecular Weight (MW)

458.0

Formula

C24H32ClN5O2

CAS No.

1001264-89-6 (free base);

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 92 mg/mL (200.9 mM)

Water: <1 mg/mL

Ethanol: 92 mg/mL (200.9 mM)

Other info

InChi Key: GRZXWCHAXNAUHY-NSISKUIASA-N
InChi Code: InChI=1S/C24H32ClN5O2/c1-15(2)26-13-19(17-4-6-18(25)7-5-17)24(32)30-10-8-29(9-11-30)23-21-16(3)12-20(31)22(21)27-14-28-23/h4-7,14-16,19-20,26,31H,8-13H2,1-3H3/t16-,19-,20-/m1/s1
SMILES Code: O=C(N1CCN(C2=C([C@H](C)C[C@H]3O)C3=NC=N2)CC1)[C@@H](C4=CC=C(Cl)C=C4)CNC(C)C

Synonym/Chemical Name

GDC0068; GDC-0068; GDC 0068; RG7440; RG-7440; RG 7440; (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-(propan-2-ylamino)propan-1-one

In Vitro

Kinase Assay: 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.

Cell Assay: The biologic activity of GDC-0068 was evaluated in cell-based assays in vitro . Similar to other ATP-competitive Akt inhibitors, GDC-0068 induced a dose-dependent increase in Akt phosphorylation at both Thr308 (T308) and Ser 473 (S473) residues in all cell lines tested, including lines in which the PI3K/Akt pathway is activated, such as PC-3 (PTEN homozygous deletion mutant, prostate), BT474M1 (PIK3CAK111N mutant and HER2-amplified, breast), IGROV-1 (PTENT319fsX1/Y155C and PIK3CA1069 W, ovarian).

Testing against a broad panel of 230 kinases, GDC-0068 only inhibits 3 kinases by>70% at 1 μM concentration (PRKG1α, PRKG1β, and p70S6K, with IC50 of 98 nM, 69 nM, and 860 nM, respectively). GDC-0068 displays>100-fold selectivity for Akt over PKA with IC50 of 3.1 μM. In LNCaP, PC3 and BT474M1 cells, GDC-0068 treatment inhibits the phosphorylation of the Akt substrate, PRAS40 with IC50 of 157 nM, 197 nM, and 208 nM, respectively. Furthermore, GDC-0068 selectively inhibits cell cycle progression and viability of cancer cell lines driven by Akt signaling, including those with defects in the tumor suppressor PTEN, oncogenic mutations in PIK3CA, and amplification of HER2, with strongest effects in HER2+ and Luminal subtypes

In Vivo

Oral administration of GDC-0068 in PC3 prostate tumor xenografts model induces down-regulation of p-PRAS40. In BT474-Tr xenografts, GDC-0068 treatment reduces pS6 and peIF4G levels, re-localizes FOXO3a to nucleus, and induces feedback upregulation of HER3 and pERK. Administration of GDC-0068 exhibits potent antitumor efficacy in multiple xenograft tumor models, including the PTEN-deficient prostate cancer models LNCaP and PC3, the PIK3CA H1047R mutant breast cancer model KPL-4, and MCF7-neo/HER2 tumor model

Animal model

Female nude mice bearing LNCaP, PC3, KPL-4, or MCF7 tumor xenografts

Formulation & Dosage

Dissolved in 0.5% methylcellulose/0.2% Tween-80; 100 mg/kg; oral taken

References

[1] Lin K. Cancer Res, 2011, 71(8 Supplement), abstract DDT02-01.