SCH727965 (Dinaciclib) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH727965 were sufficient for long-lasting cellular effects. SCH727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. These results suggest that SCH727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent.
|Cell lines||A2780 cells|
|Preparation method||dThd uptake growth inhibition assay.
A2780 cells were maintained in DMEM (Cellgro) plus 10% fetal bovine serum (HyClone) and passaged twice weekly by detaching the monolayer with trypsin-EDTA (Life Technologies). One hundred microliters of A2780 cells (5 × 103 cells) were added per well to a 96-well Cytostar-T plate (Amersham) and incubated for 16 to 24 hours at 37°C. Compounds were serially diluted in complete media plus 2% 14C-labeled dThd (Amersham). Media were removed from the Cytostar T plate; 200 μL of various compound dilutions were added in quadruplicate; and the cells were incubated for 24 hours at 37°C. Accumulated incorporation of radiolabel was assayed using scintillation proximity and measured on a TopCount (Packard/Perkin-Elmer Life Sciences). The percentage of dThd uptake inhibition, relative to a vehicle control, was calculated and plotted on log-linear plots to allow derivation of IC50 values.
|Incubation time||16 to 24 h|
|Animal models||A2780 cells xenograft model in mice|
|Dosages||8, 16, 32, and 48 mg/kg daily for 10 d|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥76 mg/mL|
|Source||Mol Cancer Ther (2014). Figure 2. SCH727965|
|Cell Lines||U937 cells|
|Incubation Time||3 h|
|Results||As shown in Fig. 2A, exposure to SCH727965 failed to block XBP-1s mRNA induction in multiple thapsigargin-treated leukemia and myeloma cell lines, for example, U937, K562, 8226, and BaF3/T315I.|
|Source||Mol Cancer Ther (2014). Figure 1. SCH727965|
|Cell Lines||U937 cells|
|Incubation Time||16 h|
|Results||SCH727965-mediated reductions in XBP-1s and Grp78 expression were also observed in U937 cells exposed to another ER stress inducer, tunicamycin|
The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells.
Johnson et al. Leukemia. 2012 May 30. PMID: 22791353.
The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells.
Fu et al. Mol Cancer Ther. 2011 Jun;10(6):1018-27. PMID: 21490307.
Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor.
Parry D, et al. Mol Cancer Ther. 2010 Aug;9(8):2344-53. PMID: 20663931.
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