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M2698 (M-2698, MSC2363318A) HCl, the hydrochloride salt of M2698, is a novel, oral and ATP competitive dual inhibitor of the serine/threonine protein kinases ribosomal protein S6 Kinase (p70S6K) and Akt (protein kinase B) with anticancer activity.
| Targets |
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| ln Vitro |
M2698, which has an IC50 of 0.02-8.5 μM, inhibits the growth of breast carcinoma cell lines in a dose-dependent manner during a 72-hour period (0.3 nM to 50 M) [1]. M2698 (0.3, 1 μM; 24 hours) phosphorylates the Akt feedback loop, inhibits Akt activity, and suppresses p70S6K activity in breast cancer cell lines [1]. M2698 suppresses pGSK3β (IC50=17 nM) and pS6 (IC50= 15 nM) in an indirect manner[1].
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| ln Vivo |
M2698 (10–30 mg/kg/day; taken orally for 28 days) inhibits tumor growth in a dose-dependent manner and, at dosages up to 30 mg/kg, promotes tumor regression [1]. M2698 (20 mg/kg/day; orally for 4 days) causes a rise in pAkt levels in tumor tissue and causes a tumor:plasma exposure ratio of 12:1 in less than 24 hours [1]. The average total concentrations of M2698 in the brain and plasma of rats were 1750 ng/g and 175 ng/mL, respectively, after 16 hours of infusion [1]. After a single dosage or daily therapy for seven days, M2698 (oral; 1, 5, 10, or 20 mg/kg/day) suppresses S6 phosphorylation in a dose-proportional manner over time [1].
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Breast tumors cell lines Tested Concentrations: 0.3 nM to 50 M Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited proliferation in a dose-dependent manner. Western Blot Analysis[1] Cell Types: HCC1419 and MDA-MB -453 cells Tested Concentrations: 0.3, 1 µM Incubation Duration: 24 hrs (hours) Experimental Results: Inhibited p70S6K activity and induced feedback loop phosphorylation on Akt and suppressed Akt activity in breast cancer cell lines. |
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| Animal Protocol |
Animal/Disease Models: Female nude mice bearing MDA-MB-468 tumors[1]
Doses: 10, 20 and 30 mg/kg Route of Administration: PO; daily; for 28 days Experimental Results: Resulted in dose-dependent inhibition of tumor growth and resulted in tumor regression with the highest dose of 30 mg/kg. Animal/Disease Models: Female SCID Beige mice with MDA-MB-453 xenografted[1] Doses: 20 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: Daily; for 4 days Experimental Results: Had a tumor :plasma exposure ratio of 12:1 over 24 hrs (hours). |
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| References | ||
| Additional Infomation |
M-2698 is under investigation in clinical trial NCT01971515 (First-in-Human Dose Escalation Trial in Subjects With Advanced Malignancies).
Rupitasertib is an orally available inhibitor of the serine/threonine protein kinases ribosomal protein S6 Kinase (p70S6K) and Akt (protein kinase B), with potential antineoplastic activity. Upon administration, rupitasertib binds to and inhibits the activity of p70S6K and Akt. This prevents the activation of the PI3K/Akt/p70S6K signaling pathway and inhibits tumor cell proliferation in cancer cells that have an overactivated PI3K/Akt/p70S6K signaling pathway. Constitutive activation and dysregulated signaling of the PI3K/Akt/p70S6K pathway are frequently associated with tumorigenesis of many tumor types; targeting multiple kinases in this pathway is more efficacious than targeting a single kinase. |
| Molecular Formula |
C21H19CLF3N5O
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|---|---|
| Molecular Weight |
449.85667347908
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| Exact Mass |
449.123
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| CAS # |
1379545-95-5
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| Related CAS # |
1379545-95-5;M2698 HCl;
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| PubChem CID |
89808643
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| Appearance |
White to off-white solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
635
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1C=CC(=CC=1C(F)(F)F)[C@@H](CN1CCC1)NC1C2C=CC=C(C(N)=O)C=2N=CN=1
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| InChi Key |
HXAUJHZZPCBFPN-QGZVFWFLSA-N
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| InChi Code |
InChI=1S/C21H19ClF3N5O/c22-16-6-5-12(9-15(16)21(23,24)25)17(10-30-7-2-8-30)29-20-14-4-1-3-13(19(26)31)18(14)27-11-28-20/h1,3-6,9,11,17H,2,7-8,10H2,(H2,26,31)(H,27,28,29)/t17-/m1/s1
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| Chemical Name |
4-[[(1S)-2-(azetidin-1-yl)-1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl]amino]quinazoline-8-carboxamide
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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: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), 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 : ~125 mg/mL (~277.86 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.62 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 20.8 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: ≥ 2.08 mg/mL (4.62 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2229 mL | 11.1146 mL | 22.2291 mL | |
| 5 mM | 0.4446 mL | 2.2229 mL | 4.4458 mL | |
| 10 mM | 0.2223 mL | 1.1115 mL | 2.2229 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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