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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 500mg |
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Ipatasertib dihydrochloride, also known as GDC-0068, is a brand-new, highly effective, orally bioavailable, ATP-competitive, and selective pan-Akt inhibitor that targets Akt1/2/3. In cell-free assays, it had an IC50 of 5 nM, 18 nM, or 8 nM and demonstrated 620-fold selectivity over PKA. Cancers in humans are treated with GDC-0068. The PI3K-AKT pathway controls tumorigenesis, cell survival, and growth. When GDC-0068 binds to and inhibits the activation of AKT, the cell cycle is arrested, tumor cell proliferation is inhibited, and tumor cell death is induced. Because the PI3K-AKT pathway is frequently activated in tumors, GDC-0068 has a high affinity for tumors with PTEN or PI3K mutations that activate AKT.
| Targets |
Akt1 (IC50 = 5 nM); Akt3 (IC50 = 8 nM); Akt2 (IC50 = 18 nM); PKA (IC50 = 3100 nM)
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| ln Vitro |
Over 600-fold and over 100-fold, respectively, more selective for Akt1 at IC50 than for the closely related PKA and p70S6K, is exhibited by imatasertib diHClide. Ipatasertib diHClide inhibited only three protein conjugates (PRKG1α, PRKG1β, and p70S6K) by more than 70% at 1 μM in a panel of 230 protein conjugates, including 36 members of the human AGC family. ..For these three species, the IC50 values that were periodically measured were 98, 69, and 860 nM, in that order. Hence, in comparison to the next most potent non-Akt inhibitor, p70S6K Multiples panel above, ipatasertib dihydrochloride is 100 times more selective for Akt1 in the screen, with the exception of PKG1 (where ipatasertib dihydrochloride has >10-fold greater Akt1 selectivity). Three xenograft models demonstrating dose-dependent responses to drug treatment were used to study the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of ipatasertib dihydrochloride: MCF7-neo. The average cell viability IC50 of /HER2, TOV-21G.x1, and LNCaP Ipatasertib diHClide in these three cell lines were 2.56, 0.44, and 0.11 μM, respectively [2].
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| ln Vivo |
In transplantation models where Akt is triggered by genetic changes such as PTEN loss, PIK3CA mutations or mutations, or HER2 overexpression, imatinib diHClide is often successful. The tumors in these models developed slowly, were generated, or reverted at or below 100 mg/kg, the maximum well-tolerated dose observed in immunocompromised mice. When examined in vivo, the daily combination of RP-56976 with Ipatasertib diHClide produced analgesia and tumor regression in PC-3 and MCF7-neo/HER2 xenograft mice, but the toxin by itself was either ineffective or just caused the tumor to develop. gradually increasing dosages. Similarly, when Ipatasertib diHClide and NSC 241240 were coupled, a rise in TGI was seen in an OVCAR3 ovarian cancer xenograft model. Compared to treatment with extra chemotherapy, Ipatasertib diHClide in combination with RP-56976 or NSC 241240 alone resulted in less than 5% weight loss [2].
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| Cell Assay |
The 384-well plates are seeded with 2,000 cells per well in a volume of 54 L, and then incubated overnight (roughly 16 hours) at 37°C with 5% CO2. To create the desired stock concentrations, compounds (like Ipatasertib) are diluted in DMSO before being added in a volume of 6 L per well. Each treatment is tested four times. After four days of incubation, total luminescence is measured on a Wallac Multilabel Reader, and relative viability is estimated using CellTiter-Glo. The 4-parameter curve analysis (XLfit) is used to calculate the drug concentration that produces an IC50 and is based on the results of a minimum of three experiments. The highest concentration tested (10 M) is listed for cell lines that failed to reach an IC50[2].
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| Animal Protocol |
Mice：Numerous patient-derived xenograft models and tumor cell line models are used to evaluate in vivo efficacy. Immunocompromised mice have cells or tumor fragments implanted subcutaneously into their flanks. Mice that are severely combined immunodeficient (SCID) or beige, or both, are used. Male mice are castrated prior to the implantation of tumor fragments, and the LuCaP35V patient-derived primary tumors are obtained. When tumor cells or fragments are implanted into mice, the tumors are watched until they reach mean tumor volumes of 180 to 350 mm3 and are then divided into groups of 8 to 10 animals each. Ipatasertib is administered every day (QD) via oral (per os; PO) gavage and is formulated in 0.5% methylcellulose/0.2% Tween-80 (MCT). Every week (QW), 2.5 or 7.5 mg/kg of RP-56976 is administered intravenously (IV) in a solution of 3% EtOH/97% saline. Saline-based NSC 241240 is administered intraperitoneally (IP) once a week at a dose of 50 mg/kg.
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| References |
[1]. Blake JF, et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem. 2012 Sep 27;55(18):8110-27.
[2]. Lin J, et al. Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013 Apr 1;19(7):1760-72 |
| Molecular Formula |
C₂₄H₃₄CL₃N₅O₂
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|---|---|
| Molecular Weight |
530.9181
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| Exact Mass |
529.1778
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| Elemental Analysis |
C, 54.30; H, 6.46; Cl, 20.03; N, 13.19; O, 6.03
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| CAS # |
1396257-94-5
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| Related CAS # |
Ipatasertib;1001264-89-6
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| Appearance |
Solid powder
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| SMILES |
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.[H]Cl.[H]Cl
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| InChi Key |
SRKVNRNRVFDUTG-VISIQVHMSA-N
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| InChi Code |
InChI=1S/C24H32ClN5O2.2ClH/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,8-13H2,1-3H32*1H/t16-,19-,20-/m1../s1
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| Chemical Name |
(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-onedihydrochloride
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| Synonyms |
Ipatasertib dihydrochloride; Ipatasertib; GDC 0068; GDC-0068; GDC0068; RG7440; RG 7440; RG-7440
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (188.35 mM; Need ultrasonic)
H2O: ≥41 mg/mL (77.22 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.88 mg/mL (7.31 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3.88 mg/mL (7.31 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.92 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (3.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: ≥ 2.08 mg/mL (3.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 6: 16.67 mg/mL (31.40 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8835 mL | 9.4176 mL | 18.8352 mL | |
| 5 mM | 0.3767 mL | 1.8835 mL | 3.7670 mL | |
| 10 mM | 0.1884 mL | 0.9418 mL | 1.8835 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02465060 | Active Recruiting |
Drug: Adavosertib Drug: Afatinib Drug: Afatinib Dimaleate |
Bladder Carcinoma Breast Carcinoma |
National Cancer Institute (NCI) |
August 12, 2015 | Phase 2 |
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