| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| Other Sizes |
|
Purity: ≥98%
Momelotinib (formerly CYT-387; CYT-11387; LM-1149; Ojjaara), an aminopyrimidine analog, is a novel, potent and ATP-competitive inhibitor of Janus kinases (JAK1/2) with potential antitumor and anti-inflammatory activity. It inhibits JAK1/2 with IC50s of 11 nM/18 nM, and shows ~10-fold selectivity for JAK1/2 over JAK3. CYT 387 is currently undergoing Phase I/II clinical trials for treating myelofibrosis. Momelotinib shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. It was discovered by high-throughput enzyme and cell-based screening along with the optimization using structure-guided medicinal chemistry. Momelotinib (Ojjaara) was approved in 2023 by FDA for treating Myelofibrosis in adults with anaemia.
| ln Vitro |
Momelotinib (CYT387) has an IC50 of 1400 nM, which suppresses the proliferation of parental Ba/F3 cells (Ba/F3-wt) triggered by IL-3. Furthermore, Momelotinib (CYT387), with an IC50 of 200, reduces the proliferation of cell lines activated by JAK2 or MPL signaling, such as Ba/F3-MPLW515L cells, CHRF-288-11 cells, and Ba/F3-TEL-JAK2 cells. 700 nM, 1 nM, and nM. Furthermore, it has been demonstrated that momelotinib (CYT387), with an IC50 of 2 μM–4 μM, also potently inhibits the formation of erythrocyte colonies in individuals with JAK2V617F-positive PV in vitro [1]. IGF-1 and IL-6-induced Ras/MAPK and PI3K/AKT activation are inhibited by momelotinib (CYT387). Additionally, in primary multiple myeloma (MM) cells, momelotinib (CYT387) promotes apoptosis as a single agent and synergizes with conventional anti-MM medications PS-341 and L-PAM [2].
|
||
|---|---|---|---|
| ln Vivo |
Momelotinib (CYT387) corrected hematocrit, spleen size, white blood cell count, and physiological levels of inflammatory cytokines in a mouse model of MPN [3].
|
||
| Animal Protocol |
|
||
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Momelotinib is rapidly absorbed following oral administration with a bioavailability of 97%. The mean (%CV) steady-state Cmax is 479 ng/mL (61%), and the mean (%CV) AUC is 3,288 ng x h/mL (60%) at the maximum recommended dosage. Momelotinib exposure (i.e., Cmax and AUC) increases dose proportionally from 100 mg to 300 mg (0.5 to 1.5 times the maximum recommended dosage), but less than dose-proportional at doses from 400 mg to 800 mg (two to four times the maximum recommended dosage). There is no clinically significant accumulation. The Tmax at steady state is two hours (Q1: 1 hour; Q3: 3 hours) post-dose. No clinically significant differences in momelotinib pharmacokinetics were observed following administration of either a high-fat meal (800 kcal; 50% fat) or low-fat meal (400 kcal; 20% fat) in healthy subjects. Momelotinib is primarily eliminated in feces and, to a lesser extent, in urine. Following a single oral dose of radiolabeled momelotinib in healthy subjects, about 69% of the total radioactive dose was recovered in fecesm with M14 accounting for 21.4% of the dose, momelotinib and M21 each accounting for 13%, and other 12 metabolites accounting for the remaining 22%. About 28% of radioactivity was recovered in urine, with M21 being the major species. The mean (%CV) apparent volume of distribution at steady-state is 984 L (118%). The mean (%CV) clearance is clearance is 103 L/h (87%). Metabolism / Metabolites Momelotinib is metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%). M21 is initially formed via oxidation of the morpholine ring by the same CYP enzymes, followed by metabolism via aldehyde oxidase. M21 is a major metabolite in humans that retains approximately 40% of the pharmacological activity of the parent. The mean ratio of M21 to momelotinib for AUC ranged from 1.4 to 2.1. Momelotinib can undergo amide hydrolysis, N-dealkylation, nitrile hydrolysis, nitrile oxidation, and glucuronidation. Biological Half-Life The elimination half-life of momelotinib and the M21 metabolite is four to eight hours. |
||
| Toxicity/Toxicokinetics |
Hepatotoxicity
In the published preregistration clinical trials of momelotinib, rates of serum ALT or AST elevations ranged from 21% to 31% and were above 5 times the upper limit of normal (ULN) in 0.5% to 2.0%, and above 20 times ULN in 0.5%. Two of 448 momelotinib treated patients evaluated in the safety cohort developed clinically apparent, but self-limiting liver injury with jaundice. A third patient developed liver injury with jaundice that appeared to be due to reactivation of hepatitis B. The liver injury was typically hepatocellular without immune allergic or autoimmune features, arising after 2 to 4 months of therapy, and resolving soon after drug discontinuation. Peak ALT elevations ranged from 308 to 1178 U/L and peak bilirubin from 2.3 to 7.0 mg/dL. There were no deaths from hepatic failure. Since its approval and more widespread clinical use, there have been no further reports of serum enzyme or bilirubin elevations or instances of clinically apparent liver injury, but it has been available for a limited time only. Likelihood score: D (possible cause of clinically apparent liver injury including reactivation of hepatitis B). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of momelotinib during breastfeeding. Because momelotinib is 91% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during momelotinib therapy and for at least 1 week after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Momelotinib is 91% bound to plasma proteins in healthy volunteers. |
||
| References |
|
||
| Additional Infomation |
Pharmacodynamics
Momelotinib inhibits Janus Kinase 1 and 2 (JAK1/JAK2) with an IC50 of 11 and 18 nM, respectively. It also inhibits JAK3 (IC50 = 155 nM) and tyrosine kinase 2 (TYK2) (IC50 = 17 nM) with less selectivity. Momelotinib inhibited STAT3 phosphorylation in whole blood from patients with myelofibrosis (MF). Maximal inhibition of STAT3 phosphorylation occurred two hours after momelotinib dosing, which persisted for at least six hours. Iron availability and erythropoiesis were assessed by analysis of circulating hepcidin concentrations: an acute and sustained reduction of circulating hepcidin was observed for the duration of the 24-week administration of momelotinib to patients with MF. |
| Molecular Formula |
C23H22N6O2
|
|---|---|
| Molecular Weight |
414.46
|
| Exact Mass |
414.18
|
| CAS # |
1056634-68-4
|
| Related CAS # |
Momelotinib sulfate;1056636-06-6;Momelotinib Mesylate;1056636-07-7
|
| PubChem CID |
25062766
|
| Appearance |
Light yellow to yellow solid powder
|
| Density |
1.3±0.1 g/cm3
|
| Index of Refraction |
1.646
|
| LogP |
1.22
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
31
|
| Complexity |
615
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
ZVHNDZWQTBEVRY-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C23H22N6O2/c24-10-12-25-22(30)18-3-1-17(2-4-18)21-9-11-26-23(28-21)27-19-5-7-20(8-6-19)29-13-15-31-16-14-29/h1-9,11H,12-16H2,(H,25,30)(H,26,27,28)
|
| Chemical Name |
N-(cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide.
|
| Synonyms |
LM-1149 , CYT-11387; LM 1149 , CYT 11387; LM1149 , CYT11387; CYT-387; Momelotinib; Momelotinib free base; CYT387; CYT 387; Ojjaara
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 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 25.0 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: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4128 mL | 12.0639 mL | 24.1278 mL | |
| 5 mM | 0.4826 mL | 2.4128 mL | 4.8256 mL | |
| 10 mM | 0.2413 mL | 1.2064 mL | 2.4128 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 |
| NCT02244489 | Terminated | Drug: Momelotinib (MMB) Drug: Capecitabine |
Relapsed/Refractory Metastatic Pancreatic Ductal Adenocarcinoma |
Sierra Oncology LLC - a GSK company |
November 5, 2014 | Phase 1 |
| NCT02206763 | Terminated | Drug: Momelotinib (MMB) Drug: Erlotinib |
EGFR Mutated EGFR TKI Naive Metastatic NSCLC |
Sierra Oncology LLC - a GSK company |
October 16, 2014 | Phase 1 |
| NCT01998828 | Terminated | Drug: Larotrectinib Sulfate Procedure: Bone Scan |
Drug: Momelotinib | Polycythemia Vera Essential Thrombocythemia |
February 19, 2014 | Phase 2 |
| NCT02258607 | Terminated | Drug: Momelotinib (MMB) Drug: Trametinib |
Relapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer |
Sierra Oncology LLC - a GSK company |
March 11, 2015 | Phase 1 |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
