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| Targets |
Vevorisertib triHCl targets AKT (also known as protein kinase B), a key serine/threonine kinase in the PI3K/AKT/mTOR signaling pathway. It is a pan-AKT inhibitor, meaning it inhibits all three isoforms (AKT1, AKT2, AKT3). It also inhibits the AKT1-E17K mutant. The compound is a selective, allosteric inhibitor.
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| ln Vitro |
Inhibiting AKT1-E17K phosphorylation, vevorisertib triHClide (0, 12, 33, 111, 333, 1000 nM, 2 hours) [1]. AKT-WT and AKT1-E17K plasma membrane translocation is inhibited by vevorisertib triHClide (1 μM) for two hours in NIH 3T3 cells transfected with pcDNAAKT-WT-GFP or pcDNA-E17K-GFP, whether growth factors are present or not [1]. Full-length AKT1 is 57% inhibited by vevorisertib triHCle (5 μM) [1]. Vevorisertib triHClide (0, 0.012, 0.037, 0.11, 0.33, 1 μM; 2 hours) affects AKT direct substrates, such as PRAS40, GSK3β, FOXO, BAD, and AS160, and mTORC1 in cancer cell lines in a dose-dependent manner [1]. Vevorisertib triHClide (GI50 < 1 μM) inhibits the growth of cancer cells in the head and neck, breast, and esophageal regions [1]. In PIK3CA mutant cell lines, vevorisertib triHClide demonstrates strong antiproliferative action [1]. In gastrointestinal stromal tumor (GIST) cells, vevorisertib triHCl (MK-4440)/imatinib mesylate (IM) combination exhibits cell cycle arrest and enhanced cell death [2]. With PIK3CA mutant cell lines, vevorisertib triHClide demonstrates potent antiproliferative activity [1]: GI50 (nM) PIK3CA ER PR HER2 T47D 1.05 H1047R + + - EFM-19 1.54 H1047R + + - MCF-7 2.20 E545K + + - BT474 3.25 K111N + + + MDA-MB-453 6.05 H1047R - - +
In vitro, Vevorisertib triHCl potently inhibits AKT phosphorylation. It has Kd values of 1.2 nM for AKT1 and 8.6 nM for AKT1-E17K. It has IC50 values of 0.55 nM for AKT1, 0.81 nM for AKT2, and 1.3 nM for AKT3. It is effective in cancers harboring AKT mutations or PTEN loss. |
| ln Vivo |
Vevorisertib triHClide (25, 50 and 75 mg/kg; oral; 5 days on and then 4 days off for 20 days) indicated effective tumor growth suppression of 68%, 78% and 98%, respectively [1]. Vevorisertib triHClide (5, 10, 20, 40, 80 and 120 mg/kg; given orally daily for ten days) exhibited tumor growth inhibition of 29%, 33%, 50%, 73%, 83% and 92%, respectively. [1]. Vevorisertib triHCl has a Cmax plasma concentration of ≥2 μM [1]. Vevorisertib triHClide is generally well tolerated at dose levels up to 120 mg/kg [1]. Compared with either single drug, the Vevorisertib triHClide (MK-4440)/IM combination showed greater efficacy in preclinical models of IM-sensitive GIST [2].
In vivo, Vevorisertib triHCl has demonstrated antitumor activity in preclinical and early clinical studies. At oral doses of 25, 50, and 75 mg/kg (5 days on, 4 days off, for 20 days), it showed potent tumor growth inhibition of 68%, 78%, and 98%, respectively. It shows potential as a targeted therapy for solid tumors with dysregulated AKT signaling. |
| Enzyme Assay |
The in vitro kinase assay for Vevorisertib triHCl involves measuring its binding affinity (Kd) to AKT1, AKT2, AKT3, and AKT1-E17K, and its inhibition of AKT kinase activity (IC50). Binding is assessed using surface plasmon resonance or similar techniques. Kinase activity is measured using phosphorylation of a substrate peptide.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: 293T cells (transiently transfected with pcDNA-E17K-GFP) Tested Concentrations: 0, 12, 33, 111, 333. 1000 nM Incubation Duration: 2 hrs (hours) Experimental Results: AKT1-E17K phosphorylation is inhibited. Western Blot Analysis[1] Cell Types: Cancer Cell Types: MDA-MB 453 (PIK3CAH1047R; Her2 amp), NCI-H1650 (PTEN null), KU-19-19 (AKT1-E17K&E49K; NRas Q61R) Tested Concentrations: 0, 0.012 , 0.037, 0.11, 0.33, 1 μM Incubation Duration: 2 hrs (hours) Experimental Results: Displayed dose-dependent effects on mTORC1 and AKT direct substrates including PRAS40, GSK3β, FOXO, BAD and AS160. In vitro cell-based assays for Vevorisertib triHCl involve treating cancer cells with the compound and measuring AKT phosphorylation levels, downstream signaling (e.g., mTOR, PRAS40), and cell viability. The compound’s effects on cell proliferation and apoptosis are evaluated in AKT-dependent cancer cell lines. |
| Animal Protocol |
Animal/Disease Models: Endometrial PDX mouse xenograft model (AKT1-E17K mutant tumor fragments are subcutaneously (sc) (sc) implanted into athymic nude mice; tumor volume is approximately 200 mm3) [1]
Doses: 25, 50 and 75 mg/kg Route of Administration: po; 5 days of dosing, followed by a 4-day dosing holiday, for a total of 20 days. Experimental Results: demonstrated effective tumor growth inhibition of 68%, 78% and 98% respectively. Animal/Disease Models: AN3CA mouse xenograft model (female NCr nu/nu mouse with tumor size 250 mm3) [1] Doses: 5, 10, 20, 40, 80 and 120 mg/kg Route of Administration: Oral; daily Once, the results lasted for ten days: showing tumor growth inhibition of 29%, 33%, 50%, 73%, 83% and 92% respectively. In vivo animal studies for Vevorisertib triHCl involve xenograft mouse models of cancer. Tumor-bearing mice are treated orally with the compound at doses of 25, 50, or 75 mg/kg. Tumor growth inhibition is monitored, and AKT phosphorylation and downstream signaling are assessed in tumor tissues. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Vevorisertib triHCl are not detailed in the provided literature. The compound is orally active.
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| Toxicity/Toxicokinetics |
No specific toxicity data for Vevorisertib triHCl are available in the provided literature. The compound is for research use only.
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| References |
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| Additional Infomation |
Vevorisertib triHCl is a pan-AKT and AKT1-E17K mutant inhibitor. It has Kd values of 1.2 nM (AKT1) and 8.6 nM (AKT1-E17K). It shows potent antitumor activity in preclinical models. It is for research use only. Its CAS number is 1416775-08-0.
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| Molecular Formula |
C35H41CL3N8O
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|---|---|
| Molecular Weight |
696.11
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| Exact Mass |
694.246
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| CAS # |
1416775-08-0
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| Related CAS # |
Vevorisertib;1416775-46-6
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| PubChem CID |
131746460
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| Appearance |
White to yellow solid powder
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
47
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| Complexity |
976
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| Defined Atom Stereocenter Count |
0
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| SMILES |
NC1N=CC=CC=1C1=NC2=CC=C(C3C=CC=C(N4CCC(N(C)C(=O)C)CC4)C=3)N=C2N1C1C=CC(C2(CCC2)N)=CC=1.Cl.Cl.Cl
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| InChi Key |
HNFNJTGXAZHZSB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C35H38N8O.3ClH/c1-23(44)41(2)26-15-20-42(21-16-26)28-7-3-6-24(22-28)30-13-14-31-34(39-30)43(33(40-31)29-8-4-19-38-32(29)36)27-11-9-25(10-12-27)35(37)17-5-18-35;;;/h3-4,6-14,19,22,26H,5,15-18,20-21,37H2,1-2H3,(H2,36,38);3*1H
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| Chemical Name |
N-[1-[3-[3-[4-(1-aminocyclobutyl)phenyl]-2-(2-aminopyridin-3-yl)imidazo[4,5-b]pyridin-5-yl]phenyl]piperidin-4-yl]-N-methylacetamide;trihydrochloride
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~150 mg/mL (~215.48 mM)
H2O : ~25 mg/mL (~35.91 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5.25 mg/mL (7.54 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.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 52.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5.25 mg/mL (7.54 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 52.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4366 mL | 7.1828 mL | 14.3655 mL | |
| 5 mM | 0.2873 mL | 1.4366 mL | 2.8731 mL | |
| 10 mM | 0.1437 mL | 0.7183 mL | 1.4366 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.
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