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| Targets |
MKC-1 targets multiple cellular proteins: tubulin (causing microtubule destabilization), members of the importin β family (involved in transnuclear protein transport), and also inhibits the activation of Akt (protein kinase B) and the mTOR signaling pathway. [2]
In pancreatic cancer studies, MKC-1 is described as a cell cycle inhibitor with downstream targets including tubulin and the importin-β family. [1] |
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| ln Vitro |
MKC-1 demonstrates broad-spectrum antitumor effects against a wide range of human tumor cell lines (more than 30), including five out of five multidrug-resistant cell lines. [2]
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| ln Vivo |
Mice with Caki-1 renal cell xenograft tumors had a much longer median survival time (MST) when administered MKC-1 (200 mg/kg, orally, once a day) [3].
MKC-1 has demonstrated anti-tumor activity in 15 in vivo preclinical models. [2] In a Phase 2 open-label study of patients with unresectable or metastatic pancreatic cancer who had failed at least one prior chemotherapy regimen, MKC-1 was administered orally. No objective responses were observed per RECIST criteria; one patient (enrolled in the continuous dosing part) demonstrated stable disease. Among 20 patients, median overall survival was 101 days (range 19–506 days, 95% CI: 57–151 days), and median time to progression was 42 days (range 14–104 days, 95% CI: 22–49 days). The tumor antigen CA19-9 showed no patient with a ≥50% decrease. [1] |
| Toxicity/Toxicokinetics |
In a Phase 2 study of MKC-1 in advanced pancreatic cancer, the most common adverse events considered related or possibly related to MKC-1 administration were hematologic toxicities and fatigue. One patient developed grade 5 (fatal) pancytopenia. Grade 3 and 4 events included cytopenias (lymphopenia, anemia), hyperbilirubinemia, pneumonia, mucositis, fatigue, infusion reaction, anorexia, and hypoalbuminemia. Among the four patients treated with continuous twice-daily fixed dosing (90 mg morning, 60 mg evening), two developed grade 1/2 lymphopenia, and no grade 3, 4, or 5 toxicities of any kind were observed in this small subset. [1]
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| References |
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| Additional Infomation |
MKC-1 (formerly known as Ro 31-7453) is an orally available small molecule cell cycle inhibitor. Its multiple mechanisms of action include arresting cellular mitosis and inducing apoptosis by binding to tubulin (causing microtubule destabilization) and members of the importin β family, as well as inhibiting the activation of Akt and the mTOR pathway. [2]
In a Phase 2 study for advanced pancreatic cancer, the initial dosing schedule was 100 mg/m² twice daily for 14 consecutive days of a 28-day cycle. This was later modified to fixed and continuous dosing of 150 mg per day (90 mg every morning and 60 mg every evening) in 28-day cycles. Accrual was discontinued after 20 patients due to lack of responses by RECIST criteria and observed toxicities. The study concluded that MKC-1 did not demonstrate sufficient activity in advanced pancreatic cancer to warrant further exploration. [1] |
| Molecular Formula |
C22H16N4O4
|
|---|---|
| Molecular Weight |
400.39
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| Exact Mass |
400.117
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| CAS # |
125313-92-0
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| PubChem CID |
5327686
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| Appearance |
Orange to red solid powder
|
| LogP |
3.944
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
30
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| Complexity |
805
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
OVSKGTONMLKNPZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H16N4O4/c1-24-10-15(13-5-3-4-6-17(13)24)19-20(22(28)23-21(19)27)16-11-25(2)18-9-12(26(29)30)7-8-14(16)18/h3-11H,1-2H3,(H,23,27,28)
|
| Chemical Name |
3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-1H-pyrrole-2,5-dione
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| Synonyms |
MKC1 MKC-1MKC 1 R 440 R-440 R440 Ro-317453 Ro317453Ro 317453
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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 : ≥ 50 mg/mL (~124.88 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4976 mL | 12.4878 mL | 24.9756 mL | |
| 5 mM | 0.4995 mL | 2.4976 mL | 4.9951 mL | |
| 10 mM | 0.2498 mL | 1.2488 mL | 2.4976 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 |
| NCT00506402 | COMPLETED | Drug: MKC-1 | Agnogenic Myeloid Metaplasia Hematological Malignancies Myelodysplasia |
CASI Pharmaceuticals, Inc. | 2006-11 | Phase 1 |
| NCT00306631 | COMPLETED | Drug: MKC-1 | Breast Cancer | CASI Pharmaceuticals, Inc. | 2006-01 | Phase 2 |
| NCT00656461 | COMPLETED | Drug: MKC-1 | Advanced Cancer | CASI Pharmaceuticals, Inc. | 2008-03 | Phase 1 |
| NCT00568646 | COMPLETED | Drug: MKC-1 | Pancreatic Cancer | CASI Pharmaceuticals, Inc. | 2007-11 | Phase 2 |
| NCT00607607 | COMPLETED | Drug: MKC-1 | Endometrial Cancer Ovarian Cancer |
CASI Pharmaceuticals, Inc. | 2008-01 | Phase 2 |
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