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| 25mg |
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Purity: ≥98%
COTI-2 is an orally available, third-generation small molecule activator of the mutant p53 protein (a tumor suppressor). It has potential anti-cancer activity because it can restore the mutant p53 protein to its wild-type conformation. An additional AKT2 inhibitor is COTI-2. Both in vitro and in vivo testing has shown that COTI-2 is highly effective against numerous cancer cell lines from a variety of human cancers. Additionally, it showed better efficacy when compared to conventional chemotherapeutic and targeted-therapeutic agents and a low toxicity profile in mice. Early research on COTI-2's mechanism of action shows that it is neither a conventional kinase inhibitor nor an inhibitor of the Hsp90 protein, but instead kills cancer cells by inducing apoptosis. Clinical trials are currently being conducted with COTI-2.
| Targets |
p53
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|---|---|
| ln Vitro |
The thiosemicarbazone COTI-2 is said to encourage the refolding of mutant p53 and restore the function of wild-type p53. At nanomolar concentrations, it is effective against human tumor cell lines originating from a variety of sources and causes cell death through apoptosis[1]. Both in vitro and in vivo, COTI-2 is incredibly effective against a variety of cancer cell lines from a wide range of human cancers. Over 200 kinases from important cancer-related kinase pathways evaluated in both kinase assays were not significantly inhibited by COTI-2, and COTI-2 did not inhibit Hsp90's ATPase activity, a widely distributed molecular chaperone crucial to cell survival and cell cycle regulation[2].
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| ln Vivo |
At a dose of 10 mg/kg, COTI-2 significantly slowed the growth of the xenografts of the human colorectal tumor HT-29. At doses as low as 3 mg/kg, COTI-2 also markedly slowed the growth of the tumor in the SHP-77 SCLC xenograft model. OVCAR-3, MDA-MB-231, and U87-MG xenograft growth are all delayed by its treatment. A secure toxicity profile is shown in vivo by COTI-2 treatment. As shown by the in vitro data, COTI-2 selectively targets a wide range of human cancer cell lines while having minimal negative effects on normal cells[2].
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| Enzyme Assay |
The interaction of COTI-2 with 227 kinases is tested using the AMBIT BIOSCIENCES KINOMESCAN assay. In a brief, affinity resins for kinase assays are produced by treating streptavidin-coated magnetic beads with biotinylated small molecule ligands for 30 min at 25°C. The liganded beads are blocked with excess biotin and then washed in blocking buffer (1% BSA, 0.05% Tween 20, 1 mM DTT), which helps to remove unbound ligand and lessen non-specific binding. In one binding buffer (20% SeaBlock, 0.17× PBS, 0.05% Tween 20, 6 mM DTT), phage lysates, liganded affinity beads, and COTI-2 are combined. In a final volume of 0.1 mL, all reactions are conducted in polystyrene 96-well plates that have already been pre-treated with blocking buffer.
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| Cell Assay |
For 48 hours, SHP-77 cells were cultured with different COTI-2 concentrations. The cells were then stained with Annexin V and 7AAD after being washed twice with 1X cold PBS. In a nutshell, 1 × 105 cells were treated with 5 l of Annexin V and 7AAD, and they were then left to sit in the dark at room temperature for 15 minutes. A 400 μl dose of the 1X binding buffer was then injected into the cells.
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| Animal Protocol |
SHP-77 and HT-29 cells are injected into the flanks of NCr-nu mice (2×106 cells per injection site) using 50% matrigel (n = 5 mice per group). With regard to SHP-77 xenografts, COTI-2 therapy is started before palpable tumors appear. Animals are given 3 mg/kg of COTI-2 (once every two days, up to 38 days) a day after SHP-77 cells are injected into them. Standard caliper measurements are used to estimate the size of tumors at 5, 10, 17, 24, and 38 days. The ability of COTI-2 to inhibit the growth of established tumors is evaluated in the context of HT-29 xenografts. Before beginning IP treatment with COTI-2 (10 mg/kg, 5 days a week for 7 weeks) or saline IP, HT-29 xenografts are allowed to reach a size of 200 mm3. Every 4 days, caliper measurements are used to measure tumor growth.
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| References | |
| Additional Infomation |
Mutant p53 Activator COTI-2 is an orally available third generation thiosemicarbazone and activator of mutant forms of the p53 protein, with potential antineoplastic activity. Upon oral administration, mutant p53 activator COTI-2 targets and binds to the misfolded mutant forms of the p53 protein, which induces a conformational change that normalizes p53 and restores its activity. This induces apoptosis in tumor cells in which the p53 protein is mutated. In addition, COTI-2 inhibits the activation of Akt2 and prevents the activation of the PI3K/AKT/mTOR pathway, thereby inducing apoptosis in cancer cells in which this pathway is overexpressed. p53, a tumor suppressor protein, plays a key role in controlling cellular proliferation and survival. High levels of mutant p53 are seen in many cancers and are associated with uncontrolled cellular growth.
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| Molecular Formula |
C19H22N6S
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|---|---|---|
| Molecular Weight |
366.48
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| Exact Mass |
366.162
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| Elemental Analysis |
C, 62.27; H, 6.05; N, 22.93; S, 8.75
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| CAS # |
1039455-84-9
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| Related CAS # |
1204956-74-0 (HCl);1039455-84-9;
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| PubChem CID |
91810660
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
574.1±60.0 °C at 760 mmHg
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| Flash Point |
301.0±32.9 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.715
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| LogP |
0.79
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
26
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| Complexity |
516
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S=C(N/N=C1\C2C(=CC=CN=2)CCC\1)N1CCN(C2C=CC=CN=2)CC1
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| InChi Key |
UTDAKQMBNSHJJB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H22N6S/c26-19(23-22-16-7-3-5-15-6-4-10-21-18(15)16)25-13-11-24(12-14-25)17-8-1-2-9-20-17/h1-2,4,6,8-10H,3,5,7,11-14H2,(H,23,26)
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| Chemical Name |
N-(6,7-dihydro-5H-quinolin-8-ylideneamino)-4-pyridin-2-ylpiperazine-1-carbothioamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.67 mg/mL (1.83 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 6.7 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 | 2.7287 mL | 13.6433 mL | 27.2866 mL | |
| 5 mM | 0.5457 mL | 2.7287 mL | 5.4573 mL | |
| 10 mM | 0.2729 mL | 1.3643 mL | 2.7287 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 | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02433626 | Unknown | Drug: COTI2 Drug: Cisplatin |
Ovarian Cancer HNSCC |
Critical Outcome Technologies Inc. | December 2015 | Phase 1 |
A.COTI-2, a third generation thiosemicarbazone, was designed using the CHEMSAS computational platform.B.Human cancer cell lines were treated with COTI-2.Tumor cell proliferation was examined 72 h after treatment with COTI-2. The IC50values were calculated from four independent experiments. Error bars indicate SEM.Oncotarget. 2016 Jul 5; 7(27): 41363–41379. |
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COTI-2 is significantly more effective than cetuximab or erlotinib in inhibiting colorectal cancer cell line proliferation.Oncotarget. 2016 Jul 5; 7(27): 41363–41379. |
Human glioblastoma cell lines are sensitive to COTI-2 treatment.Oncotarget. 2016 Jul 5; 7(27): 41363–41379. |
COTI-2 induces apoptosis in human cancer cells.Oncotarget. 2016 Jul 5; 7(27): 41363–41379. |
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COTI-2 treatment inhibits human HT-29 and SHP-77 xenograft growth.Oncotarget. 2016 Jul 5; 7(27): 41363–41379. |
COTI-2 treatment delays U87-MG xenograft growth.Oncotarget. 2016 Jul 5; 7(27): 41363–41379. |
COTI-2 treatment inhibits OVCAR-3 xenograft growth.Oncotarget. 2016 Jul 5; 7(27): 41363–41379. |
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COTI-2 demonstrates a safe toxicity profilein vivo.Oncotarget. 2016 Jul 5; 7(27): 41363–41379. |
Refolding and reactivation of missense-mutant p53.Nat Rev Cancer.2018 Feb;18(2):89-102. |
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