WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 200786
CAS#: 1056634-68-4 (free base)
Description: Momelotinib, also known as CYT387, is an inhibitor of Janus kinases JAK1 and JAK2, acting as an ATP competitor with IC50 values of 11 and 18 nM, respectively. The inhibitor is significantly less active towards other kinases, including JAK3 (IC50 = 0.16 μM). As of 2011, CYT387 is being developed as a drug for myelofibrosis and currently undergoes Phase I/II clinical trials. Additional potential treatment indications for CYT387 include other myeloproliferative neoplasms, cancer (solid and liquid tumors) and inflammatory conditions.
MedKoo Cat#: 200786
Name: Momelotinib free base
CAS#: 1056634-68-4 (free base)
Chemical Formula: C23H22N6O2
Exact Mass: 414.18042
Molecular Weight: 414.46
Elemental Analysis: C, 66.65; H, 5.35; N, 20.28; O, 7.72
Related CAS #: 1056634-68-4 (free base) 1380317-28-1 (HCl)
Synonym: CTY387; CYT-387; CYT 387; CYT11387; CYT-11387; CYT 11387; Momelotinib; Momelotinib free base
IUPAC/Chemical Name: N-(cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide.
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)
SMILES Code: O=C(NCC#N)C1=CC=C(C2=NC(NC3=CC=C(N4CCOCC4)C=C3)=NC=C2)C=C1
Appearance: Yellow solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, DMF
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | Momelotinib (CYT387) is an ATP-competitive inhibitor of JAK1/JAK2 with IC50a of 11 nM and 18 nM, respectively. |
| In vitro activity: | Momelotinib showed the strongest inhibition of proliferation of CLL cells. JAK, BTK, and PI3Kδ inhibitors did not induce cell death in CLL cells (Fig. 1B). As expected, JAK inhibitors were not able to reduce resistance to venetoclax and fludarabine after coculture of CLL cells on CD40L-fibroblasts because CD40 signaling is not mediated by JAKs (Fig. 1C). Treatment with both JAK inhibitors but not BTK or PI3Kδ inhibitors led to a reduction in p-STAT6 induced by IL-4 (Fig. 1D). Surprisingly, momelotinib treatment also led to a reduction in IgM-induced p-Akt and p-S6 levels, although not as strong as both BTK inhibitors or idelalisib. Ruxolitinib did not affect BCR signaling to Akt or S6, demonstrating different modes of action of these JAK inhibitors. These results demonstrate that JAK inhibitors are not cytotoxic for CLL cells by themselves, but are able to influence signaling of prosurvival cytokines like IL-4 and IL-21 that induce proliferation and IgM expression, and momelotinib was able to partially block BCR signaling. Reference: J Immunol. 2019 Oct 15;203(8):2100-2109. https://www.jimmunol.org/content/203/8/2100.long |
| In vivo activity: | In order to more precisely establish the in vivo efficacy of CYT387 in a treatment resistant setting, this study used subcutaneous allografts of cells excised from Th-MYCN or Th-MYCNCPM32 tumors in 129 × 1/SvJ (immunocompetent, strain-matched) mice. As expected, Th-MYCNCPM32 allografts were refractory to CPM treatment with a 160% mean growth at 7 days after treatment (Fig. 6A), while Th-MYCN allografts underwent complete regression at a dose of 32 mg/kg CPM. In contrast, treatment with 32 mg/kg CPM (once per week) together with 50 mg/kg CYT387 (administered 5 days on 2 days off) significantly reduced tumor volume at day 5 in the treatment resistant Th-MYCNCPM32 allografts from a mean of 152% ± 21% to 82% ± 20% (Fig. 6B). Furthermore, this study observed an increase in survival of 6 days (representing of 37%) from a median of 16 days to a median of 22 days (Fig. 6C). These results establish that the acquisition of chemoresistance following treatment with CPM is transplantable, therefore cell-intrinsic, and that in vivo treatment with the JAK STAT inhibitor CYT387 reduces tumor growth and extends survival in CPM chemoresistant neuroblastoma. Reference: Cancer Res. 2019 Oct 15;79(20):5382-5393. https://cancerres.aacrjournals.org/content/79/20/5382.long |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 16.0 | 38.6 |
The following data is based on the product molecular weight 414.46 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Hofland T, de Weerdt I, Ter Burg H, de Boer R, Tannheimer S, Tonino SH, Kater AP, Eldering E. Dissection of the Effects of JAK and BTK Inhibitors on the Functionality of Healthy and Malignant Lymphocytes. J Immunol. 2019 Oct 15;203(8):2100-2109. doi: 10.4049/jimmunol.1900321. Epub 2019 Sep 11. PMID: 31511358. 2. Giordano G, Parcesepe P, D'Andrea MR, Coppola L, Di Raimo T, Remo A, Manfrin E, Fiorini C, Scarpa A, Amoreo CA, Conciatori F, Milella M, Caruso FP, Cerulo L, Porras A, Pancione M. JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer. J Exp Clin Cancer Res. 2019 Jan 22;38(1):28. doi: 10.1186/s13046-018-1019-5. PMID: 30670049; PMCID: PMC6343337. 3. Schwartz BE, Rajagopal V, Smith C, Cohick E, Whissell G, Gamboa M, Pai R, Sigova A, Grossman I, Bumcrot D, Sasidharan K, Romeo S, Sehgal A, Pingitore P. Discovery and Targeting of the Signaling Controls of PNPLA3 to Effectively Reduce Transcription, Expression, and Function in Pre-Clinical NAFLD/NASH Settings. Cells. 2020 Oct 7;9(10):2247. doi: 10.3390/cells9102247. PMID: 33036387; PMCID: PMC7600576. 4. Yogev O, Almeida GS, Barker KT, George SL, Kwok C, Campbell J, Zarowiecki M, Kleftogiannis D, Smith LM, Hallsworth A, Berry P, Möcklinghoff T, Webber HT, Danielson LS, Buttery B, Calton EA, da Costa BM, Poon E, Jamin Y, Lise S, Veal GJ, Sebire N, Robinson SP, Anderson J, Chesler L. In Vivo Modeling of Chemoresistant Neuroblastoma Provides New Insights into Chemorefractory Disease and Metastasis. Cancer Res. 2019 Oct 15;79(20):5382-5393. doi: 10.1158/0008-5472.CAN-18-2759. Epub 2019 Aug 12. PMID: 31405846. |
| In vitro protocol: | 1. Hofland T, de Weerdt I, Ter Burg H, de Boer R, Tannheimer S, Tonino SH, Kater AP, Eldering E. Dissection of the Effects of JAK and BTK Inhibitors on the Functionality of Healthy and Malignant Lymphocytes. J Immunol. 2019 Oct 15;203(8):2100-2109. doi: 10.4049/jimmunol.1900321. Epub 2019 Sep 11. PMID: 31511358. 2. Giordano G, Parcesepe P, D'Andrea MR, Coppola L, Di Raimo T, Remo A, Manfrin E, Fiorini C, Scarpa A, Amoreo CA, Conciatori F, Milella M, Caruso FP, Cerulo L, Porras A, Pancione M. JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer. J Exp Clin Cancer Res. 2019 Jan 22;38(1):28. doi: 10.1186/s13046-018-1019-5. PMID: 30670049; PMCID: PMC6343337. |
| In vivo protocol: | 1. Schwartz BE, Rajagopal V, Smith C, Cohick E, Whissell G, Gamboa M, Pai R, Sigova A, Grossman I, Bumcrot D, Sasidharan K, Romeo S, Sehgal A, Pingitore P. Discovery and Targeting of the Signaling Controls of PNPLA3 to Effectively Reduce Transcription, Expression, and Function in Pre-Clinical NAFLD/NASH Settings. Cells. 2020 Oct 7;9(10):2247. doi: 10.3390/cells9102247. PMID: 33036387; PMCID: PMC7600576. 2. Yogev O, Almeida GS, Barker KT, George SL, Kwok C, Campbell J, Zarowiecki M, Kleftogiannis D, Smith LM, Hallsworth A, Berry P, Möcklinghoff T, Webber HT, Danielson LS, Buttery B, Calton EA, da Costa BM, Poon E, Jamin Y, Lise S, Veal GJ, Sebire N, Robinson SP, Anderson J, Chesler L. In Vivo Modeling of Chemoresistant Neuroblastoma Provides New Insights into Chemorefractory Disease and Metastasis. Cancer Res. 2019 Oct 15;79(20):5382-5393. doi: 10.1158/0008-5472.CAN-18-2759. Epub 2019 Aug 12. PMID: 31405846. |
1: Durmus S, Xu N, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387. Pharmacol Res. 2013 Oct;76:9-16. doi: 10.1016/j.phrs.2013.06.009. Epub 2013 Jul 1. PubMed PMID: 23827160.
2: Pardanani A, Laborde RR, Lasho TL, Finke C, Begna K, Al-Kali A, Hogan WJ, Litzow MR, Leontovich A, Kowalski M, Tefferi A. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013 Jun;27(6):1322-7. doi: 10.1038/leu.2013.71. Epub 2013 Mar 5. PubMed PMID: 23459451; PubMed Central PMCID: PMC3677140.
3: Sparidans RW, Durmus S, Xu N, Schinkel AH, Schellens JH, Beijnen JH. Liquid chromatography-tandem mass spectrometric assay for the JAK2 inhibitor CYT387 in plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 May 1;895-896:174-7. doi: 10.1016/j.jchromb.2012.03.021. Epub 2012 Mar 23. PubMed PMID: 22476054.
4: Monaghan KA, Khong T, Burns CJ, Spencer A. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia. 2011 Dec;25(12):1891-9. doi: 10.1038/leu.2011.175. Epub 2011 Jul 26. PubMed PMID: 21788946.
5: Tyner JW, Bumm TG, Deininger J, Wood L, Aichberger KJ, Loriaux MM, Druker BJ, Burns CJ, Fantino E, Deininger MW. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood. 2010 Jun 24;115(25):5232-40. doi: 10.1182/blood-2009-05-223727. Epub 2010 Apr 12. PubMed PMID: 20385788; PubMed Central PMCID: PMC2892953.
6: Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009 Aug;23(8):1441-5. doi: 10.1038/leu.2009.50. Epub 2009 Mar 19. PubMed PMID: 19295546.
CYT387 is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases (IC(50)=11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC(50)=155 nM). CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC(50) approximately 1500 nM) or Ba/F3-MPLW515L cells (IC(50)=200 nM), but has considerably less activity against BCR-ABL harboring K562 cells (IC=58 000 nM). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba/F3-TEL-JAK2) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba/F3-TEL-JAK3), and STAT-5 phosphorylation was inhibited in HEL cells with an IC(50)=400 nM. Furthermore, CYT387 selectively suppressed the in vitro growth of erythroid colonies harboring JAK2V617F from polycythemia vera (PV) patients, an effect that was attenuated by exogenous erythropoietin. Overall, research data indicate that the JAK1/JAK2 selective inhibitor CYT387 has potential for efficacious treatment of MPN harboring mutated JAK2 and MPL alleles. [source: Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia. 2009 Aug;23(8):1441-5. Epub 2009 Mar 19. or http://www.ncbi.nlm.nih.gov/pubmed/19295546]
