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CAS No.: 1702809-17-3

THZ531 Catalog No. CSN20480

Synonyms: THZ531

THZ531 is a covalent CDK12 and CDK13 inhibitor with IC50s of 158 nM and 69 nM.

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技术信息

生物活性

描述Cyclin-dependent kinases (CDKs) are a family of protein kinases which along with their regulatory subunit cyclins play a key role in the growth, development, proliferation and death of eukaryotic cells and are responsible for insuring integrity in the coordination of events through the cell cycle^[2]. The results from Kinase assays demonstrate that THZ531 potently inhibits CDK12 and CDK13 with IC₅₀s of 158 nM and 69 nM, respectively; whereas inhibition of CDK7 and CDK9 is more than 50-fold weaker with IC₅₀s of 8.5 and 10.5 µM, respectively^[3]. THZ531 treatment leads to a dramatic and irreversible decrease in Jurkat cell proliferation with an IC₅₀ of 50 nM. FACS cell cycle analysis following treatment with escalating doses of THZ531 displays a dose and time-dependent increase in the number of cells exhibiting sub-G1 content. At 50 nM THZ531, no increase in the percentage of apoptotic cells is observed over DMSO control for the time course of the experiment. Higher doses of THZ531 leads to pronounced Annexin V signal with 30 to 40% annexin V-positively stained cells by 72 hours. A dramatic reduction in elongating Pol II following THZ531 treatment is also observed^[3].
作用机制THZ531 binds to M816 in the kinase hinge region and connects to Cys1039 in two conformations via the compound's flexible linker.
参考文献

[1] Zhang T, Kwiatkowski N, et al. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol. 2016 Oct;12(10):876-84.
[2] Misra RN, Xiao Hy, Rawlins DB, Shan W, Kellar KA, Mulheron JG, Sack JS, Tokarski JS, Kimball SD, Webster KR. 1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2405-8. doi: 10.1016/s0960-894x(03)00381-0. PMID: 12824044.
[3] Zhang T, Kwiatkowski N, Olson CM, Dixon-Clarke SE, Abraham BJ, Greifenberg AK, Ficarro SB, Elkins JM, Liang Y, Hannett NM, Manz T, Hao M, Bartkowiak B, Greenleaf AL, Marto JA, Geyer M, Bullock AN, Young RA, Gray NS. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol. 2016 Oct;12(10):876-84. doi: 10.1038/nchembio.2166. Epub 2016 Aug 29. PMID: 27571479; PMCID: PMC5033074.

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
- 1.7919 mL
- 8.9594 mL
- 17.9188 mL
- 5 mM
- 0.3584 mL
- 1.7919 mL
- 3.5838 mL
- 10 mM
- 0.1792 mL
- 0.8959 mL
- 1.7919 mL

技术信息

CAS号

1702809-17-3

储存条件

粉末: Keep in dark place,Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C30H32ClN7O2

运输

蓝冰

分子量

558.07

别名

THZ531

溶解度

DMSO	100.0 mg/mL (179.2 mM)
Water	Insoluble
Ethanol	100.0 mg/mL (179.2 mM)

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