532372 Cdk7 Inhibitor VIII, THZ1 - Calbiochem

532372
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Overview

Replacement Information

Key Spec Table

Empirical Formula
C₃₁H₂₈ClN₇O₂ •4HCl

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      Glass bottle 10 mg
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      Description
      OverviewA cell-permeable, non-toxic, phenylaminopyrimidinyl-acrylamide compound that acts as a highly potent, selective, ATP-site directed, and irreversible inhibitor of Cdk7 (IC50 = 3.2 nM). Acts by allosterically and covalently modifying Cys312 located outside the canonical kinase domain. Shown to block the phosphorylation of Ser5 and Ser7 in RNAPII CTD, the intracellular substrate of Cdk7 (< 250 nM, 4 h in Jurkat cells). Does not affect the activity of C312S mutated Cdk7. Exhibits comparatively week activity towards Cdk12 (IC50 = 250 nM), Cdk1, and Cdk2. Suppresses the proliferation and cell viability of T-ALL and CLL cell lines and induces apoptosis with significant reduction in the levels of MCL-1 and XIAP. Also induces a significant reduction in the transcript and protein levels of RUNX1, TAL, and GATA3 (~ 50 nM). Suppresses the growth of KOPTK1 cells xenografts in murine model (10 mg/kg, b.i.d).

      Please note that the molecular weight for this compound is batch-specific due to variable water content.
      Catalogue Number532372
      Brand Family Calbiochem®
      Synonyms(E)-N-(3-(5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide, 4HCl, THZ1, HCl
      References
      ReferencesKwiatkowski, N., et al. 2014. Nature 511, 616.
      Chipumuro, E., et al. Cell 159, 1126.
      Product Information
      FormYellow solid
      Hill FormulaC₃₁H₂₈ClN₇O₂ •4HCl
      Chemical formulaC₃₁H₂₈ClN₇O₂ •4HCl
      Hygroscopic Hygroscopic
      ReversibleN
      Quality LevelMQ100
      Applications
      Biological Information
      Primary TargetCdk7
      Secondary targetCdk12
      Purity≥96% by HPLC
      Physicochemical Information
      Cell permeableY
      Dimensions
      Materials Information
      Toxicological Information
      Safety Information according to GHS
      Safety Information
      Product Usage Statements
      Storage and Shipping Information
      Ship Code Ambient Temperature Only
      Toxicity Standard Handling
      Storage -20°C
      Protect from Light Protect from light
      Hygroscopic Hygroscopic
      Do not freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
      Packaging Information
      Packaged under inert gas Packaged under inert gas
      Transport Information
      Supplemental Information
      Specifications

      Documentation

      Cdk7 Inhibitor VIII, THZ1 - Calbiochem SDS

      Title

      Safety Data Sheet (SDS) 

      Cdk7 Inhibitor VIII, THZ1 - Calbiochem Certificates of Analysis

      TitleLot Number
      532372

      References

      Reference overview
      Kwiatkowski, N., et al. 2014. Nature 511, 616.
      Chipumuro, E., et al. Cell 159, 1126.

      Brochure

      Title
      NPI Flyer- Epigenetics and Nuclear Function Feature
      New Products - Antibodies, Small Molecule, Inhibitors (MM)

      Technical Info

      Title
      White Paper: Further considerations of antibody validation and usage.
      Data Sheet

      Note that this data sheet is not lot-specific and is representative of the current specifications for this product. Please consult the vial label and the certificate of analysis for information on specific lots. Also note that shipping conditions may differ from storage conditions.

      Revision19-December-2014 JSW
      Synonyms(E)-N-(3-(5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide, 4HCl, THZ1, HCl
      DescriptionA cell-permeable, acrylamide-bearing phenylaminopyrimidine that, despite its ATP-competitive affinities toward multiple kinases (IC50 ≤1 µM against ATP probe binding to 22 kinases in a KiNativ panel screening), only effectively acts as an irreversible inhibitor against Cdk7 & Cdk12, and likely also Ckd13 & Cdk19, due to conformational positioning of a C-terminal Cys outside the kinase domain (C312 of human & murine Cdk7; C1539, C1517, C349 of human Cdk12, Cdk13, Cdk19, respectively) adjacent to the drug′s acrylamide moiety in the ATP cleft, allowing covalent bond formation. Due to the irreversible mode of action, 3 to 5 h incubation is shown to most effectively inhibit intracellular Ckd7 & Cdk12 (Effective conc. 100 to 500 nM in 293A, HeLa S3, Jurkat, and Loucy cultures). Likewise, drug washout following THZ1 incubation is demonstrated not to affect its potency against cellular Cdk7 substrates phosphorylatio(RNAPII S2/5/7, Cdk1 T161, Cdk2 T160, Cdk9 T186) or cell proliferation. A strong enrichment of factors involved in Cdk7 substrate RNAPII/RPB1-driven transcriptional regulation is found among THZ1-sensitive cell lines with T cell acute lymphoblastic leukemia (T-ALL; IC50 in nM = 0.49/KOPTK1, 0.54/Loucy, 0.61/DND-41, 50 nM/Jurkat by cellular ATP measurement post 72 incubation) that depend on RUNX1 transcription for proliferation being particularly sensitive to THZ1-induced apoptotic death. Intravenous injection is efficacious in suppression KOPTK1 proliferation in mice (by 91%;10 mg/3.3 mL/Kg/12 h, BID, for 29 d one week following cancer cells injection) in vivo without affecting animal body weight.
      FormYellow solid
      Intert gas (Yes/No) Packaged under inert gas
      Chemical formulaC₃₁H₂₈ClN₇O₂ •4HCl
      Purity≥96% by HPLC
      SolubilityDMSO (50 mg/ml). Use only fresh DMSO for reconstitution.
      Storage -20°C
      Hygroscopic
      Protect from light
      Do Not Freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
      Toxicity Standard Handling
      ReferencesKwiatkowski, N., et al. 2014. Nature 511, 616.
      Chipumuro, E., et al. Cell 159, 1126.