532372 Cdk7 Inhibitor VIII, THZ1 - Calbiochem

532372
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      Overview

      Replacement Information

      Key Specifications Table

      Empirical Formula
      C₃₁H₂₈ClN₇O₂ •4HCl

      Pricing & Availability

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      5.32372.0001
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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
          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 (EMD)
          New Products - Antibodies, Small Molecule, Inhibitors

          Technical Info

          Title
          White Paper: Further considerations of antibody validation and usage. (EMD)
          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.