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CYT387 sulfate salt

カタログ番号GC16468

JAK1およびJAK2の強力な阻害剤

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CYT387 sulfate salt 化学構造

Cas No.: 1056636-06-6

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Kinase experiment:

Glutathione-S-transferase (GST)-tagged JAK kinase domains expressed in insect cells are purified before use in a peptide substrate phosphorylation assay. Assays are carried out in 384-well optiplates using an Alphascreen Protein Tyrosine Kinase P100 detection kit and a PerkinElmer Fusion Alpha instrument[1].

Cell experiment:

Ba/F3 cells expressing JAK2V617F (Ba/F3-JAK2V617F) and MPLW515L (Ba/F3-MPLW515L) mutants, as well as CHRF-288-11 (JAK2T875N) and CMK (JAK3A572V) cells are used. The TEL/JAK2 and TEL/JAK3 fusions are generated and introduced into Ba/F3 murine cells. TheTEL/JAK2- or TEL/JAK3-transfected cells are cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS). Ba/F3 wild-type cells are cultured in RPMI containing 10% FCS supplemented with 5 ng/mL murine IL-3. Proliferation is measured using the Alamar Blue assay after incubating for 72 h at 37°C with 5% CO2[1].

Animal experiment:

Mice[2] On day 32 after bone marrow transplantation (when all mice exhibit severe leukocytosis and erythrocytosis), mice are assigned to 3 groups such that each group has equivalent average body weight and blood counts. Momelotinib (CYT387) is dissolved in NMP (120 mg/mL final; 1-methyl-2-pyrrolidinone, Chromasolv Plus). Subsequently, the Momelotinib/NMP mix is diluted with 0.14M Captisol to a concentration of 6 mg/mL and further diluted with 0.1M Captisol to a final concentration of 4 mg/mL. All 3 groups of mice (n=12 per group) are administered Momelotinib (CYT387) by oral gavage twice daily at 10- to 12-hour intervals from day 34 after bone marrow transplantation to day 82 (end of experiment). Mice receive NMP/Captisol without Momelotinib (CYT387) (0 mg/kg group), 25 mg/kg Momelotinib, or 50 mg/kg Momelotinib. At day 82 after bone marrow transplantation, all mice are euthanized for analysis except for 2 mice each from the 50 mg/kg and 25 mg/kg groups, which are taken off Momelotinib (CYT387) treatment and followed for 45 additional days. For assessment of the effects of Momelotinib (CYT387) on normal blood counts, naive Balb/c mice are administered vehicle control, 50 mg/kg, or 100 mg/kg Momelotinib (CYT387) in an identical fashion as described for the bone marrow transplant experimental mouse cohort. Peripheral blood is drawn at day 14, 28, 42, and 56 and levels of red cells, white cells, reticulocytes, granulocytes, lymphocytes, and monocytes are analyzed.

References:

[1]. Pardanani A, et al. 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, 23(8), 1441-1445.
[2]. Tyner JW, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood, 2010, 115(25), 5232-5240.
[3]. Burns CJ, et al. Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs). Bioorg Med Chem Lett. 2009 Oct 15;19(20):5887-92.

Background

モメロチニブ硫酸塩(CYT387硫酸塩)は、JAK1/JAK2のATP競争的阻害剤であり、IC50値はそれぞれ11 nM/18 nMであり、JAK3に対して10倍の選択性を持ちます(IC50=155 nM)。

モメロチニブ硫酸塩(CYT387硫酸塩)は、Ba / F3-JAK2V617Fおよび人間の赤血球性白血病(HEL)細胞の増殖を抑制します(IC50 = 1.5μM)、またはBa / F3-MPLW515L細胞(IC50 = 200 nM)。ただし、BCR-ABLを保有するK562細胞(IC50 = 58μM)およびFLT3変異を保有するMV4-11細胞に対してはかなり低い活性があります。IL-3で刺激された親和性Ba / F3細胞(Ba / F3-wt)の増殖も、IL-3依存性シグナル伝達経路が親和性細胞株で確立されていることから、IC50値が1.4μMで抑制されます[1]。

モメロチニブ硫酸塩(CYT387硫酸塩)は、疾患モデルで使用される用量の2倍(50および100 mg/kg)でも、8週間の期間において末梢血液計数にほとんど影響を与えません。中央値のプラズマピーク濃度は、低用量では7.1μM、高用量では32.1μMであり、半減期は約2時間です。12時間後のトラフレベルは25mg/kg投与時が10nMであり、50mg/kg投与時が900nMです。移植後34日目において全コーホートの平均白血球数とヘマトクリット値がBalb/cマウスの正常範囲を1 SD以上超えました。この時点で6匹が解剖されます。残りの動物では、25 mg/kgまたは50 mg/kg Momelotinib sulfate(CYT387 sulfate salt)、または車両を経口摂取により一日2回投与します(各治療群12匹)。治療開始からわずか6日後から両用量コーホートで白血球数が急速に低下し始め、20日後から赤血球比容率も低下することが明らかになりました[2]。経口投与後、モメロチニブ硫酸塩(CYT387硫酸塩)は高いプラズマ濃度を示します(Cmax=40.4μM;Tmax=4時間)、定量的な絶対的な経口生物学的利用能および表面積下曲線の半減期は2.4時間です。高い経口生物学的利用能は、モメロチニブ硫酸塩(CYT387硫酸塩)の低血液クリアランス(6.3 mL/min/kg)および肝臓での最初通過代謝に対する感受性が低いためだと考えられます[3]。

References:
[1]. Pardanani A, et al. 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, 23(8), 1441-1445.
[2]. Tyner JW, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood, 2010, 115(25), 5232-5240.
[3]. Burns CJ, et al. Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs). Bioorg Med Chem Lett. 2009 Oct 15;19(20):5887-92.

Chemical Properties

Cas No. 1056636-06-6 SDF
Chemical Name N-(cyanomethyl)-4-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]benzamide; sulfuric acid
Canonical SMILES C1COCCN1C2=CC=C(C=C2)NC3=NC=CC(=N3)C4=CC=C(C=C4)C(=O)NCC#N.OS(=O)(=O)O.OS(=O)(=O)O
Formula C23H26N6O10S2 M.Wt 610.62
溶解度 Soluble in DMSO Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 1.6377 mL 8.1884 mL 16.3768 mL
5 mM 0.3275 mL 1.6377 mL 3.2754 mL
10 mM 0.1638 mL 0.8188 mL 1.6377 mL
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