PHA-793887Pan-Cdk inhibitor CAS# 718630-59-2 |
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Quality Control & MSDS
3D structure
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| Cas No. | 718630-59-2 | SDF | Download SDF |
| PubChem ID | 46191454 | Appearance | Powder |
| Formula | C19H31N5O2 | M.Wt | 361.48 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 50 mg/mL (138.32 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | N-[6,6-dimethyl-5-(1-methylpiperidine-4-carbonyl)-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide | ||
| SMILES | CC(C)CC(=O)NC1=NNC2=C1CN(C2(C)C)C(=O)C3CCN(CC3)C | ||
| Standard InChIKey | HUXYBQXJVXOMKX-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C19H31N5O2/c1-12(2)10-15(25)20-17-14-11-24(19(3,4)16(14)21-22-17)18(26)13-6-8-23(5)9-7-13/h12-13H,6-11H2,1-5H3,(H2,20,21,22,25) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | PHA-793887 is a novel and potent inhibitor of CDK2, CDK5 and CDK7 with IC50 values of 8 nM, 5 nM and 10 nM, respectively. | ||||||
| Targets | CDK5/p25 | CDK2/CyclinA | CDK2/CyclinE | CDK7/CyclinH | CDK1/CyclinB | ||
| IC50 | 5 nM | 8 nM | 8 nM | 10 nM | 60 nM | ||
PHA-793887 Dilution Calculator
PHA-793887 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.7664 mL | 13.832 mL | 27.664 mL | 55.3281 mL | 69.1601 mL |
| 5 mM | 0.5533 mL | 2.7664 mL | 5.5328 mL | 11.0656 mL | 13.832 mL |
| 10 mM | 0.2766 mL | 1.3832 mL | 2.7664 mL | 5.5328 mL | 6.916 mL |
| 50 mM | 0.0553 mL | 0.2766 mL | 0.5533 mL | 1.1066 mL | 1.3832 mL |
| 100 mM | 0.0277 mL | 0.1383 mL | 0.2766 mL | 0.5533 mL | 0.6916 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Description:
IC50: PHA-793887 is a novel and potent inhibitor of CDK2, CDK5 and CDK7 with IC50 values of 8 nM, 5 nM and 10 nM, respectively.
Cyclin dependent kinases (CDKs) are a family of serine/threonine kinases that, in concert with cyclins (positive regulators) and natural inhibitors (CDKI), control the cell cycle progression.1Deregulation of the activity of CDKs, mainly due to alterations of expression and/or genetic mutations of cyclins, CDKs, CDKIs and other components of the retinoblastoma protein (pRB) pathway, has been reported in more than 90% of human neoplasms.
In vitro: PHA-793887 was found to be cytotoxic for leukemic cell lines in vitro, with IC50 ranging from 0.3 to 7 μM (mean: 2.9 μM), regardless of any specific chromosomal aberration. At these doses, the drug was not cytotoxic for normal unstimulated peripheral blood mononuclear cells or CD34+ hematopoietic stem cells. Moreover, in colony assays PHA-793887 showed very high activity against leukemia cell lines, with an IC50<0.1 μM (mean: 0.08 μM), indicating that it has efficient and prolonged antiproliferative activity. PHA-793887 induced cell-cycle arrest, inhibited Rb and nucleophosmin phosphorylation, and modulated cyclin E and cdc6 expression at low doses (0.2-1 μM) and induced apoptosis at the highest dose (5 μM) [1].
In vivo: PHA-793887 was also effective in vivo in both subcutaneous xenograft and primary leukemic disseminated models that better mimic naturally occurring human disease. Interestingly, in one disseminated model derived from a relapsed Philadelphia-positive acute lymphoid leukemia patient, PHA-793887 showed strong therapeutic activity also when treatment was started after establishment of high disease burden. Thus, PHA-793887 has promising therapeutic activity against acute leukemias in vitro and in vivo [1].
Clinical trial: A first in man, phase I dose-escalation study indicates that although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses≥44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity. These findings shows that PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development [2].
References:
[1] Alzani R, Pedrini O, Albanese C, Ceruti R, Casolaro A, Patton V, Colotta F, Rambaldi A, Introna M, Pesenti E, Ciomei M, Golay J. Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models. Exp Hematol. 2010;38(4):259-269.e2.
[2] Massard C, Soria JC, Anthoney DA, Proctor A, Scaburri A, Pacciarini MA, Laffranchi B, Pellizzoni C, Kroemer G, Armand JP, Balheda R, Twelves CJ. A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011;10(6):963-70.
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A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors.[Pubmed:21368575]
Cell Cycle. 2011 Mar 15;10(6):963-70.
BACKGROUND: PHA-793887 is an inhibitor of multiple cyclin dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887. RESULTS: Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses >/=44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity. PATIENTS AND METHODS: Cohorts of three to six patients were treated at doses of 11, 22, 44 and 66 mg/m2 of PHA-793887 administered as 1-hour intravenous infusion on days 1, 8 and 15 in a 4-week cycle. Safety and pharmacokinetics were investigated. CONCLUSION: PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development.
Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models.[Pubmed:20167248]
Exp Hematol. 2010 Apr;38(4):259-269.e2.
OBJECTIVE: The aim of the work was to determine and characterize, in vitro and in vivo, the therapeutic activity of PHA-793887, a new potent pan-cdk inhibitor, in the context of hematopoietic neoplasms. MATERIALS AND METHODS: Thirteen leukemic cell lines bearing different cytogenetic abnormalities and normal hematopoietic cells were used in cytotoxicity and colony assays. The drug activity at the molecular level was analyzed by Western blotting. PHA-793887 was also tested in vivo in several leukemia xenograft models. RESULTS: PHA-793887 was cytotoxic for leukemic cell lines in vitro, with IC(50) ranging from 0.3 to 7 microM (mean: 2.9 microM), regardless of any specific chromosomal aberration. At these doses, the drug was not cytotoxic for normal unstimulated peripheral blood mononuclear cells or CD34(+) hematopoietic stem cells. Interestingly, in colony assays PHA-793887 showed very high activity against leukemia cell lines, with an IC(50) <0.1 microM (mean: 0.08 microM), indicating that it has efficient and prolonged antiproliferative activity. PHA-793887 induced cell-cycle arrest, inhibited Rb and nucleophosmin phosphorylation, and modulated cyclin E and cdc6 expression at low doses (0.2-1 microM) and induced apoptosis at the highest dose (5 microM). It was also effective in vivo in both subcutaneous xenograft and primary leukemic disseminated models that better mimic naturally occurring human disease. Interestingly, in one disseminated model derived from a relapsed Philadelphia-positive acute lymphoid leukemia patient, PHA-793887 showed strong therapeutic activity also when treatment was started after establishment of high disease burden. CONCLUSIONS: We conclude that PHA-793887 has promising therapeutic activity against acute leukemias in vitro and in vivo.
Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.[Pubmed:20153204]
Bioorg Med Chem. 2010 Mar 1;18(5):1844-53.
We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.
Transcriptional analysis of an E2F gene signature as a biomarker of activity of the cyclin-dependent kinase inhibitor PHA-793887 in tumor and skin biopsies from a phase I clinical study.[Pubmed:20423997]
Mol Cancer Ther. 2010 May;9(5):1265-73.
A transcriptional signature of the pan-cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors.
