|(8E)-6-甲基-21,22-二氢-12-氧杂-3,6-二氮杂-2(6,2)-嘧啶-1,4(1,3)-二苯环十二蕃-8-烯|CsnPharm

CAS No.: 1204918-72-8

(8E)-6-Methyl-21,22-dihydro-12-oxa-3,6-diaza-2(6,2)-pyrimidina-1,4(1,3)-dibenzenacyclododecaphan-8-ene Catalog No. CSN23736

Synonyms: TG02;TG02 (Double bond E)

TG02 (Double bond E) is the Double key form of TG02. TG02 is a small molecule potent CDK2/JAK2/FLT3 inhibitor with IC50s of 13/73/56 nM respectively.

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实验方案

技术信息

生物活性

描述CDK2 (Cyclin Dependent Kinase 2) is a member of a family of serine/threonine protein kinases that participate in cell cycle regulation. CDK2 triggers duplication of centrosomes and DNA, acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. CDK2 associates with and is regulated by other subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A), and p27Kip1 (CDKN1B). SB1317 (TG02) is a CDK2 inhibitor. Based on an enzyme assay, the inhibitory IC50 of SB1317 against CDK2 is 13 nM^[2].According to results of a cell proliferation assay, in which the incubation time is 48h, the inhibitory IC50 of SB1317 to cell viability of HL-60, Hct116, Ramos, Colo205 and DU145 cells were 59, 79, 33, 72, 140 nM, respectively. When hct116 cells were treated by 8, 40, 200, 1000 nM concentrations of SB1317 for 24h, results of a western blot method showed that SB1317 dose dependently suppressed the level of phosphor-Rb^[2]. In a xenograft model established by subcutaneous implantation of hct116 cells into Balb/c nude mice, SB1317 orally administrated at the dose of 75 mg/kg 3 times per week, starting 8 days after cell inoculation for 15 days, inhibited the growth of tumors with a mean (tumor growth inhibition rate) TGI of 82%. In a Ramos xenograft model also established by subcutaneous implantation of cells into Balb/c nude mice, SB1317 was orally administrated at the dose of 75 mg/kg on a 2 days and on 5 days off schedule or dosed via i.p. injection at 15 mg/kg on a 5 days off schedule for 15 days. The TGI were 42% for the oral delivery method and 63% for i.p.^[2].
作用机制SB1317 is a CDK2 inhibitor. According to a docking study, SB1317 occupied the ATP binding site of CDK2 kinase. SB1317 formed hydrogen bonds to the residue Leu83 and a salt bridge to Asp86^[2].
动物研究
剂量
Mice: 30 mg/kg - 60 mg/kg^[1] (p.o.)

给药途径
p.o.

动物药代数据
Animal Nude mice^[1]
Dose 30 mg/kg
Administration p.o.
C_max 74 ng/ml
AUC_{0→48 h} 363 ng·h/ml
T_max 0.5 h
参考文献

[1] Goh KC, Novotny-Diermayr V, et al. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia. 2012 Feb;26(2):236-43.
[2] William AD, Lee AC, Goh KC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Lee CP, Wang H, Williams M, Sun ET, Hu C, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW. Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer. J Med Chem. 2012 Jan 12;55(1):169-96.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.6849 mL
- 13.4243 mL
- 26.8485 mL
- 5 mM
- 0.5370 mL
- 2.6849 mL
- 5.3697 mL
- 10 mM
- 0.2685 mL
- 1.3424 mL
- 2.6849 mL

技术信息

CAS号	1204918-72-8	储存条件	粉末 Sealed in dry,2-8°C 液体 -20°C:3-6 月 -80°C:12月
分子式	C23H24N4O	运输	蓝冰
分子量	372.46	别名	TG02;TG02 (Double bond E)

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(8E)-6-Methyl-21,22-dihydro-12-oxa-3,6-diaza-2(6,2)-pyrimidina-1,4(1,3)-dibenzenacyclododecaphan-8-ene Catalog No. CSN23736

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