CDKI-73 - CAS 1421693-22-2
Catalog number: 1421693-22-2
Category: Inhibitor
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Molecular Formula:
C15H15FN6O2S2
Molecular Weight:
394.45
COA:
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Targets:
CDK
Description:
CDKI-73 was cytotoxic to all of the CLL samples tested (n = 38) with a mean LD50 value of 0.08μM ± 0.10 μM following exposure to drug for 48h. In contrast, normal B-lymphocytes (n = 10) and CD34+ normal bone marrow cells (n = 5) were significantly less susceptible to the cytotoxic effects of CDKI-73. Treatment of CLL cells with 0.1 μM CDKI-73 for 4h inhibited the phosphorylation of cdk9 and ser2 of RNA polymerase II. CDKI-73 induces a rapid loss of MCL1 protein and this is mediated by significant inhibition at the level of gene transcription. However, this inhibition is not restricted to MCL1 as similar reductions in XIAP and CCND2 were also observed following exposure to CDKI-73 for 4h. CDKI-73 rapidly inhibited cellular CDK9 kinase activity and down-regulated the RNAPII phosphorylation. CDK9 shRNA was also found to down-regulate the Mnk1 expression. Both CDKI-73 and CDK9 shRNA decreased anti-apoptotic proteins Mcl-1 and Bcl-2 and induced apoptosis. CDKI-73 exhibited a favorable pharmacokinetic profile with oral bioavailability of F = 56% following a single intravenous bolus dose at 2 mg/kg and an oral dose at 10 mg/kg in mice.
Purity:
>98%
Synonyms:
CDKI-73; CDKI 73; CDKI73.
MSDS:
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InChIKey:
GAIOPWBQKZMUNO-UHFFFAOYSA-N
InChI:
InChI=1S/C15H15FN6O2S2/c1-8-13(25-15(18-2)20-8)12-11(16)7-19-14(22-12)21-9-4-3-5-10(6-9)26(17,23)24/h3-7H,1-2H3,(H,18,20)(H2,17,23,24)(H,19,21,22)
Canonical SMILES:
CC1=C(SC(=N1)NC)C2=NC(=NC=C2F)NC3=CC(=CC=C3)S(=O)(=O)N
1.Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73.
Lam F1, Abbas AY2, Shao H2, Teo T1, Adams J1, Li P1, Bradshaw TD2, Fischer PM2, Walsby E3, Pepper C3, Chen Y4, Ding J4, Wang S5. Oncotarget. 2014 Sep 15;5(17):7691-704.
Dysregulation of cellular transcription and translation is a fundamental hallmark of cancer. As CDK9 and Mnks play pivotal roles in the regulation of RNA transcription and protein synthesis, respectively, they are important targets for drug development. We herein report the cellular mechanism of a novel CDK9 inhibitor CDKI-73 in an ovarian cancer cell line (A2780). We also used shRNA-mediated CDK9 knockdown to investigate the importance of CDK9 in the maintenance of A2780 cells. This study revealed that CDKI-73 rapidly inhibited cellular CDK9 kinase activity and down-regulated the RNAPII phosphorylation. This subsequently caused a decrease in the eIF4E phosphorylation by blocking Mnk1 kinase activity. Consistently, CDK9 shRNA was also found to down-regulate the Mnk1 expression. Both CDKI-73 and CDK9 shRNA decreased anti-apoptotic proteins Mcl-1 and Bcl-2 and induced apoptosis. The study confirmed that CDK9 is required for cell survival and that ovarian cancer may be susceptible to CDK9 inhibition strategy.
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CAS 1421693-22-2 CDKI-73

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