A3006-5mg | GDC-0068 (RG7440) [1001264-89-6] Clinisciences

Background

GDC-0068 (RG7440) is a highly selective small molecule inhibitor of Akt with IC50s of 5, 18 and 8 nM for Akt1, Akt2 and Akt3. The PI3K-AKT pathway regulates cell growth, survival and tumorigenesis. GDC-0068 binds to and blocks the activation of AKT, which result in cell cycle arrest, inhibition of tumor cell proliferation and induction of tumor cell death. PI3K-AKT is pathway frequently activated in tumors, thus tumors with PTEN or PI3K mutations, which lead to activation of AKT are with high sensitivity to GDC-0068. GDC-0068 is now used for the treatment of human cancers.

References:

1. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. JF Blake, R Xu, JR Bencsik, D Xiao… - Journal of medicinal 2012

2. Lin J, Sampath D, Nannini MA, et al: Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Canc Res 2013, 19:1760–1772.

Product Citation

1. Chenhao Geng, Xinyue Wang, et al. "Repetitive Low-Level Blast Exposure via Akt/NF-κB Signaling Pathway Mediates the M1 Polarization of Mouse Alveolar Macrophage MH-S Cells." Int J Mol Sci. 2023 Jun 25;24(13):10596. PMID: 37445774
1. Xin Zhou, Yanghao Zhong, et al. "Location-specific inhibition of Akt reveals regulation of mTORC1 activity in the nucleus." Nat Commun. 2020 Nov 30;11(1):6088. PMID:33257668

Chemical Properties

Physical Appearance	A solid
Storage	Desiccate at -20°C
M.Wt	458
Cas No.	1001264-89-6
Formula	C₂₄H₃₂ClN₅O₂
Synonyms	GDC0068,RG7440,CS0975
Solubility	≥22.9 mg/mL in DMSO; insoluble in H2O; ≥28.35 mg/mL in EtOH
Chemical Name	(2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta18pyrimidin-4-yl]piperazin-1-yl]-3-(propan-2-ylamino)propan-1-one
SDF	Download SDF
Canonical SMILES	CC1CC(C2=C1C(=NC=N2)N3CCN(CC3)C(=O)C(CNC(C)C)C4=CC=C(C=C4)Cl)O
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1]:
Cell lines	PC-3, BT474M1 and IGROV-1 cell lines
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	1 h; 25 μmol/L
Applications	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).
Animal experiment [1]:
Animal models	Nude mice
Dosage form	100 mg//kg; Oral taken
Applications	The in vitro sensitivity profile of GDC-0068 was recapitulated in vivo in xenograft models representing a spectrum of cancer types including prostate, breast, ovarian, colorectal, non–small cell lung, glioblastoma, and melanoma. GDC-0068 was typically efficacious in xenograft models in which Akt was activated because of genetic alterations including PTEN loss, PIK3CA mutations/amplifications, or HER2 overexpression. In these models, tumor growth delay, stasis, or regression was achieved at or below 100 mg/kg daily oral dose, which was the maximum dose tested in immunocompromised mice that was well tolerated.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Lin J, Sampath D, Nannini M A, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models[J]. Clinical Cancer Research, 2013, 19(7): 1760-1772.

Biological Activity

Description	Ipatasertib (GDC-0068) is a highly selective inhibitor of Akt for Akt1/2/3 with IC50 of 5 nM/18 nM/8 nM, 620-fold selectivity over PKA.
Targets	Akt1	Akt2	Akt3
IC50	5 nM	18 nM	8 nM

Quality Control

Purity = 99.06%

Chemical structure

GDC-0068 (RG7440) [1001264-89-6]

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