PHA-793887 hydrochloride
Based on 4 publication(s) in Google Scholar
PHA-793887 hydrochloride is a CDK inhibitor (with IC50 values of 8 nM for Cdk2, 60 nM for Cdk1, 62 nM for Cdk4, 138 nM for Cdk9). PHA-793887 hydrochloride inhibits purified GSK3β (IC50 79 nM). PHA-793887 hydrochloride reduces the phosphorylation level of nucleophosmin/cdc6, induces G1/G2/M phase arrest, and triggers Apoptosis by activating Caspase-3. PHA-793887 hydrochloride exhibits anticancer activity against leukemia. PHA-793887 hydrochloride can be used in research related to acute leukemia, chronic myeloid leukemia, and advanced/metastatic solid tumors.
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- CAS No.: 718630-60-5
- Formule: C19H32ClN5O2
- Masse moléculaire:397.94
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Stockage:
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Activité biologique
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Chemical Information
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- Pureté et documentation
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Publications Citing Use of MedChemExpress (MCE) PHA-793887 hydrochloride
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Activité biologique
Description
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CDK2 8 nM (IC50) |
CDK1 60 nM (IC50) |
CDK4 62 nM (IC50) |
CDK9 138 nM (IC50) |
Caspase 3 |
GSK-3β 79 nM (IC50) |
In Vitro
PHA-793887 hydrochloride potently inhibits multiple cyclin-dependent kinases with IC50 values between 5 and 140 nM, and is inactive against non-cdk kinases including c-abl, c-kit, lck, and TRKA[1].
PHA-793887 (0.01-10 μM; 48 h) hydrochloride is cytotoxic to a panel of leukemic cell lines with IC50 values from 0.04 μM to >10 μM, is not cytotoxic to unstimulated normal PBMC and CD34+ cells, and inhibits proliferation of mitogen- or growth factor-stimulated normal hematopoietic cells with IC50 values of 0.75 μM and 1.85 μM, respectively[1].
PHA-793887 (0.04-5 μM; 48 h; 24 h) hydrochloride induces G1 phase cell cycle arrest at 0.04 to 1 μM and apoptosis at 5 μM in sensitive leukemic cell lines (697, KCL22, TOM1), but has no effect on resistant KG1 cells; it activates caspase-3 in KCL22 cells at 5 μM[1].
PHA-793887 hydrochloride potently inhibits multiple CDKs, including CDK2/cyclin A (IC50 = 0.008 μM), and shows selective activity against GSK3β among a panel of non-CDK kinases[3].
PHA-793887 hydrochloride inhibits proliferation of a broad range of human cancer cell lines, with the highest potency against colon carcinoma HCT-116 cells (IC50 = 0.163 μM) and lowest potency against pancreatic carcinoma BX-PC3 cells (IC50 = 3.444 μM)[3].
PHA-793887 (1-3 μM; 24 h) hydrochloride disrupts cell cycle progression and inhibits DNA synthesis in human ovarian carcinoma A2780 cells, inducing G1 arrest at 1 μM and G2/M arrest with apoptosis at 3 μM[3].
PHA-793887 hydrochloride potently inhibits purified Cdk2 (IC50 8 nmol/L), Cdk1 (IC50 60 nmol/L), Cdk4 (IC50 62 nmol/L), Cdk9 (IC50 138 nmol/L), and GSK3β (IC50 79 nmol/L) in cell-free biochemical assays, while sparing 35 other tested kinases[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:13 leukemic cell lines (K562, KCL22, KU812, TOM1, SUP-B15, REH, 697, RS4;11, HL60, KG1, RPMI8226, ALL-2, AML-PS), normal unstimulated peripheral blood mononuclear cells (PBMC), phytohemagglutinin-stimulated PBMC, normal unstimulated CD34+ hematopoietic stem cells, growth factor cocktail-stimulated CD34+ hematopoietic stem cells
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Concentration:0.01-10 μM
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Incubation Time:48 h
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Result:Showed variable cytotoxicity across leukemic cell lines, with IC50 values ranging from 0.04 μM (most sensitive lines: TOM1, 697, RS4;11, HL60) to >10 μM (least sensitive lines: SUP-B15, KG1).
Primary leukemic cells ALL-2 and AML-PS had IC50 values of 3.4 μM and 6.2 μM, respectively.
Was not cytotoxic to unstimulated normal PBMC or CD34+ cells (IC50 >10 μM), but inhibited proliferation of stimulated PBMC (IC50 0.75 μM) and stimulated CD34+ cells (IC50 1.85 μM).
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Cell Line:697, KCL22, TOM1, and KG1 leukemic cell lines
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Concentration:0.04-5 μM
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Incubation Time:48 h (cell cycle analysis); 24 h (apoptosis analysis)
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Result:Induced G1 phase arrest (14-40% increase compared to control) and reduced S-phase cell counts at doses of 0.04 to 1 μM in sensitive cell lines (697, KCL22, TOM1).
Induced a G2/M phase block (34% increase) in TOM1 cells at 1 μM.
Induced apoptosis (15-35% sub-G1 population) in sensitive cell lines at 5 μM.
Showed no significant cell cycle arrest or apoptosis in resistant KG1 cells at any dose.
Induced caspase-3 activation (43% positive cells, a 26% increase compared to control) in KCL22 cells at 5 μM, while 0.2 μM had no effect.
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Cell Line:human ovarian carcinoma A2780 cells
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Concentration:1-3 μM
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Incubation Time:24 h
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Result:Caused a 25% increase in G0/G1 population, 76% decrease in S phase population, 62% increase in G2/M population, and 85% reduction in BrdU incorporation relative to control at 1 μM.
Caused an 11% decrease in G0/G1 population, 48% decrease in S phase population, 263% increase in G2/M population, 100% reduction in BrdU incorporation, and an increase in sub-G1 cells (from 2.6% to 26.2%) indicative of apoptosis at 3 μM.
Parmacokinetics
| Species | Dose | Route | Cmax | AUC | CL | T1/2 | Vss |
|---|---|---|---|---|---|---|---|
| Mice[3] | 10 mg/kg | i.v. | 36.5 μM | 19.2 μM·h | 23.9 mL/min/kg | 4.1 h | 1360 mL/kg |
In Vivo
PHA-793887 (20 mg/kg; i.v.; once daily; two 5-day cycles with 3-day rest between cycles) hydrochloride significantly reduces tumor growth and causes a 4.7-day growth delay in K562 subcutaneous CML xenografts in SCID mice[1].
PHA-793887 (20 mg/kg; i.v.; once daily; three 5-day cycles with 3-day rests between cycles) hydrochloride significantly increases median survival by 7 days in the preemptive disseminated AML-PS xenograft model in SCID mice[1].
PHA-793887 (20 mg/kg; i.v.; once daily; three 5-day cycles with 3-day rests between cycles) hydrochloride significantly increases median survival by 22.5 days in the preemptive disseminated ALL-2 xenograft model in SCID mice[1].
PHA-793887 (10-30 mg/kg; i.v.; daily; 10 days) hydrochloride exhibits 76% tumor growth inhibition in human A2780 ovarian carcinoma xenografts when administered at 30 mg/kg i.v. daily for 10 days, with confirmed in vivo target engagement via reduced tumor cell proliferation and pRb phosphorylation[3].
PHA-793887 (10-20 mg/kg; i.v.; daily; 10 days) hydrochloride exhibits 81% tumor growth inhibition in human HCT-116 colon carcinoma xenografts when administered at 20 mg/kg i.v. daily for 10 days, with good tolerability[3].
PHA-793887 (20 mg/kg; i.v.; daily; 10 days) hydrochloride exhibits 84% tumor growth inhibition in human BX-PC3 pancreatic carcinoma xenografts when administered at 20 mg/kg i.v. daily for 10 days, with good tolerability[3].
PHA-793887 (15-30 mg/kg; i.v.; daily; 2-10 days) hydrochloride induces dose-dependent tumor growth inhibition (50% at 15 mg/kg, 75% at 30 mg/kg) and downregulation of an E2F-dependent gene signature in A2780 ovarian carcinoma xenografts in CD-1 nude mice[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:SCID mice (unspecified gender, age not specified)[1]
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Dosage:20 mg/kg
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Administration:i.v.; once daily; 10 consecutive days
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Result:Induced tumor regression.
Achieved a tumor growth delay of 23.3 days.
Left all treated mice tumor-free one week after treatment ended.
Caused no body weight loss or toxic effects.
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Animal Model:SCID mice (unspecified gender, age not specified)[1]
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Dosage:20 mg/kg
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Administration:i.v.; once daily; two 5-day cycles with 3-day rest between cycles
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Result:Significantly reduced tumor growth from day 14 compared to vehicle controls (p < 0.01).
Achieved a tumor growth delay of 4.7 days.
Caused no body weight loss or toxic effects.
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Animal Model:SCID mice (5-week-old, unspecified gender)[1]
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Dosage:20 mg/kg
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Administration:i.v.; once daily; three 5-day cycles with 3-day rests between cycles
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Result:Significantly increased median survival time by 7 days compared to vehicle controls (p < 0.0001).
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Animal Model:SCID mice (5-week-old, unspecified gender)[1]
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Dosage:20 mg/kg
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Administration:i.v.; once daily; three 5-day cycles with 3-day rests between cycles
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Result:Significantly increased median survival time by 22.5 days compared to vehicle controls (p < 0.0001).\nSignificantly increased median survival time by 22.5 days compared to vehicle controls (p < 0.0001).
Reduced tumor infiltration from 22.5% to 1.6% in peripheral blood after two treatment cycles.
Reduced tumor infiltration from 97.7% to 24.8% in bone marrow after two treatment cycles.
Reduced tumor infiltration from 91.6% to 44.7% in spleen after two treatment cycles.
Caused no body weight loss or toxic effects.
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Animal Model:Nu/Nu (male)[3]
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Dosage:10 mg/kg; 20 mg/kg; 30 mg/kg
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Administration:i.v.; daily; 10 days
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Result:Caused dose-dependent inhibition of A2780 tumor growth, reaching 76% tumor growth inhibition at the 30 mg/kg dose at the end of treatment.
Showed marginal body weight reduction (<10% vs control mice) and no toxic effects observed at gross autopsy.
Reduced tumor BrdU incorporation (p = 0.0022) and phosphorylated retinoblastoma protein (pRb) levels (p = 0.005) in mice treated with 30 mg/kg for 5 days compared to vehicle controls.
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Animal Model:Nu/Nu (male)[3]
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Dosage:10 mg/kg; 20 mg/kg
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Administration:i.v.; daily; 10 days
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Result:Caused dose-dependent inhibition of HCT-116 tumor growth, reaching 81% tumor growth inhibition at the 20 mg/kg dose at the end of treatment.
Showed marginal body weight reduction (<10% vs control mice) and no toxic effects observed at gross autopsy.
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Animal Model:Nu/Nu (male)[3]
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Dosage:20 mg/kg
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Administration:i.v.; daily; 10 days
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Result:Caused 84% tumor growth inhibition in BX-PC3 xenografts at the end of treatment.
Showed marginal body weight reduction (<10% vs control mice) and no toxic effects observed at gross autopsy.
- Kinase activity and phosphorylation assays
- Western Blot
- Detection of Apoptosis
- TUNEL staining for apoptotic DNA fragmentation
- Flow cytometric DNA-content cell-cycle staining
- Annexin V plus membrane-impermeant dye apoptosis staining
- Apoptosis Solutions
- Protocol for Cell Cycle
- Protocol for Kinase activity and phosphorylation assays
Chemical Information
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CAS No. 718630-60-5
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Masse moléculaire 397.94
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Formule C19H32ClN5O2
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SMILES
O=C(CC(C)C)NC1=NNC2=C1CN(C2(C)C)C(C3CCN(CC3)C)=O.Cl
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Publications (4)
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Journal Impact Factor
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Most Recent
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Sci Transl Med
PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. [Abstract]2018 Jul 18;10(450):eaaq1093. PMID: 30021885 -
Sci Data
High-throughput drug screening identifies novel therapeutics for Low Grade Serous Ovarian Carcinoma. [Abstract]2024 Sep 19;11(1):1024. PMID: 39300112 -
Bioinform Biol Insights
Integrative Analysis for Identification of Therapeutic Targets and Prognostic Signatures in Non-Small Cell Lung Cancer. [Abstract]2022 Apr 6;16:11779322221088796. PMID: 35422618 -
Pureté et documentation
Références
[1]. Alzani R, et al. Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models. Experimental hematology. 2010 Apr;38(4):259-269.e2. [Content Brief]
[2]. Massard C, et al. 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 (Georgetown, Tex.). 2011 Mar 15;10(6):963-70. [Content Brief]
[3]. Brasca MG, et al. Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing. Bioorganic & medicinal chemistry. 2010 Mar 01;18(5):1844-53. [Content Brief]
[4]. Locatelli G, et al. 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. Molecular cancer therapeutics. 2010 May;9(5):1265-73. [Content Brief]
Calculators
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