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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.
Clin Cancer Res. 2018 Nov 15;24(22):5658-5672.
Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target.
SCH727965 (dinaciclib) purchased from AbMole
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Source | Clinical Cancer Research (2018 Nov). Figure 6. dinaciclib (Abmole Bioscience) |
| Method | cell viability assay | |
| Cell Lines | EGFR mutant NSCLC cell lines | |
| Concentrations | 100 nM | |
| Incubation Time | 24 h | |
| Results | MCL-1 expression was sufficient to block the ability of the dinaciclib/EGFRi combination to induce apoptosis (Fig. 6B), translating to protection of total cell viability. |
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Source | Mol Cancer Ther (2014). Figure 2. SCH727965 |
| Method | Western blot | |
| Cell Lines | U937 cells | |
| Concentrations | 2 nmol/L | |
| 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. |
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Source | Mol Cancer Ther (2014). Figure 1. SCH727965 |
| Method | Western blot | |
| Cell Lines | U937 cells | |
| Concentrations | 2 nmol/L | |
| 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 |
| Cell Experiment | |
|---|---|
| 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. |
| Concentrations | 0~500nM |
| Incubation time | 16 to 24 h |
| Animal Experiment | |
|---|---|
| Animal models | A2780 cells xenograft model in mice |
| Formulation | 20% hydroxypropyl-β-cyclodextran |
| Dosages | 8, 16, 32, and 48 mg/kg daily for 10 d |
| Administration | i.p. |
| Molecular Weight | 396.48 |
| Formula | C21H28N6O2 |
| CAS Number | 779353-01-4 |
| Solubility (25°C) | DMSO 55 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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Flavopiridol (Alvocidib) is a competitive broad-spectrum CDK inhibitor with IC50 of 30,170,100 nM against CDK1, CDK2 and CDK4, respectively. |
| R547
R547 is a potent and selective ATP-competitive CDK inhibitor, with Ki values of 2 nM, 3 nM and 1 nM for CDK1/cyclin B, CDK2/cyclin E and CDK4/cyclin D1, respectively. |
| JNJ-7706621
JNJ-7706621 is a dual cell cycle inhibitor with activity against cyclin-dependent kinases (CDK1, 2, 3, 6) with an IC50 of 3-175 nM and Aurora kinases (A and B) with an IC50 of 11-15 nM respectively. |
| PD 0332991 HCL
PD-0332991 HCl is a highly selective inhibitor of CDK4/6 with IC50 of 11 nM/16 nM in cell-free assays, respectively. It shows no activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc. |
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