P276-00CDK-1/CDK4/CDK9 inhibitor CAS# 920113-03-7 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 920113-03-7 | SDF | Download SDF |
PubChem ID | 23643975 | Appearance | Powder |
Formula | C21H21Cl2NO5 | M.Wt | 438.3 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Solubility | DMSO : 50 mg/mL (114.08 mM; Need ultrasonic) | ||
Chemical Name | 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one;hydrochloride | ||
SMILES | CN1CCC(C1CO)C2=C(C=C(C3=C2OC(=CC3=O)C4=CC=CC=C4Cl)O)O.Cl | ||
Standard InChIKey | OOVTUOCTLAERQD-OJMBIDBESA-N | ||
Standard InChI | InChI=1S/C21H20ClNO5.ClH/c1-23-7-6-12(14(23)10-24)19-15(25)8-16(26)20-17(27)9-18(28-21(19)20)11-4-2-3-5-13(11)22;/h2-5,8-9,12,14,24-26H,6-7,10H2,1H3;1H/t12-,14+;/m1./s1 | ||
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. |
P276-00 Dilution Calculator
P276-00 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.2815 mL | 11.4077 mL | 22.8154 mL | 45.6308 mL | 57.0386 mL |
5 mM | 0.4563 mL | 2.2815 mL | 4.5631 mL | 9.1262 mL | 11.4077 mL |
10 mM | 0.2282 mL | 1.1408 mL | 2.2815 mL | 4.5631 mL | 5.7039 mL |
50 mM | 0.0456 mL | 0.2282 mL | 0.4563 mL | 0.9126 mL | 1.1408 mL |
100 mM | 0.0228 mL | 0.1141 mL | 0.2282 mL | 0.4563 mL | 0.5704 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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P276-00 is a novel inhibitor for CDK-1, CDK4 and CDK9 with IC50 of 79 nM, 63 nM and 20 nM, respectively [1].
CDK (cyclin-dependent kinase) plays an important role in cell cycle progression via promoting the G1/S cell cycle transition. Many studies have shown that more CDKs are overexpressed in cancer cells than in normal cells, which explain the reason of cancer cells divide uncontrollably[2]. The overexpression of CDK1/4/6 contributes to the phosphorylation of retinoblastoma protein (RB) via binding to CCND1 and results in the release of E2F transcription of genes required for cell cycle progression [3].
P276-00 is a novel inhibitor of CDK (cyclin-dependent kinase) with the ability of arresting the cells in G1/S phase transcription. When tested with NSCLC cell lines, P276-00 showed high ability of inhibiting cell proliferate thus decreased the colony forming potential via blocking cell cycle [4]. In head and neck squamous carcinoma cell line (FaDu, Detroits-562, SCC-25), treated with P276-00 for 12 hours could significantly inhibit cell ability with IC50 value ranging from 0.8 to 1.7 uM for different cell lines via decreasing the expression of CCND1[2].
In SCID mice model with H460 xenograft, treatment of P276-00 could down regulate the expression of CDK1 thus induced tumor regression [4]. When tested with HNSCC tumor xenograft mouse model, P276-00 treatment showed anti-cancer ability with a 48% tumor growth inhibition [2].
References:
1.Manohar, S.M., et al., Cyclin-dependent kinase inhibitor, P276-00 induces apoptosis in multiple myeloma cells by inhibition of Cdk9-T1 and RNA polymerase II-dependent transcription. Leuk Res, 2011. 35(6): p. 821-30.
2.Mishra, P.B., et al., Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma. J Transl Med, 2013. 11(42): p. 1479-5876.
3.Raje, N., et al., Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma. Leukemia, 2009. 23(5): p. 961-70.
4.Shirsath, N., et al., Potentiation of anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the cyclin-dependent kinase inhibitor P276-00 in human non-small-cell lung cancer cell lines. Lung Cancer, 2013. 82(2): p. 214-21.
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Potentiation of anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the cyclin-dependent kinase inhibitor P276-00 in human non-small-cell lung cancer cell lines.[Pubmed:24051085]
Lung Cancer. 2013 Nov;82(2):214-21.
BACKGROUND: P276-00 is a novel cyclin-dependent kinase (CDK) inhibitor is in Phase II clinical trials. Valproic acid (VPA), an antiepileptic agent has been associated with anticancer activity, through the inhibition of histone deacetylase I. Here we investigate the effect of the combination of VPA and P276-00, in non-small-cell lung cancer (NSCLC) cell lines. MATERIALS AND METHODS: Cell growth inhibition was studied using the Propidium iodide (PI) assay. Cell cycle analysis and recovery were detected by flow cytometry. The expression levels of various proteins were detected by western blot. Inhibition of colony formation in H460 was checked in vitro. In vivo efficacy was studied in H460 xenograft model. RESULTS: The combination of P276-00 and VPA showed synergistic effect on p53+ and p53- NSCLC cell lines in antiproliferative assay at both constant and non-constant ratio with marked decrease in colony forming potential. Flow cytometric analysis confirmed a significant time dependent increase in apoptosis with 64% apoptotic population at 96 h compared to VPA (1%) and P276-00 (28%) alone (p < 0.0001). Incubation of the cells after treatment, in fresh medium without drugs, led to the recovery of cells treated with P276-00 alone but not the cells treated with the combination of both the drugs. The combination treatment up-regulated tumor suppressor proteins like p53, p21 and p27 along with down-regulation of proliferation and survival proteins viz. cyclin D1 and Bcl-2. This was also associated with the upregulation of the pro-apoptotic protein Bax and significant accumulation of hyperacetylated histones in the combination treatment. Interestingly, VPA in combination with P276-00 was much more effective as an antitumor agent than alone, in the H460 xenograft tumor model in SCID mice. CONCLUSIONS: This study indicates that the combination of HDAC inhibitor VPA with CDK inhibitor P276-00 is promising novel molecularly targeted therapeutic approach for NSCLC treatment.
A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma.[Pubmed:25816934]
Clin Lymphoma Myeloma Leuk. 2015 Jul;15(7):392-7.
INTRODUCTION: Overexpression of cyclin D1 is a hallmark feature of mantle cell lymphoma (MCL). Many of the oncogenic effects of cyclin D1 are mediated through cyclin-dependent kinases (CDKs). P276-00 is a potent small molecule inhibitor of CDK4-D1, CDK1-B, and CDK9-T, with promising activity in preclinical models. In phase I studies of P276-00 in patients with refractory solid neoplasms, it was well-tolerated with a mild trend toward single-agent efficacy. PATIENTS AND METHODS: A phase II study of P276-00 was conducted in patients with relapsed or refractory MCL at the recommended dose of 185 mg/m(2)/day from days 1 to 5 of a 21-day cycle. Thirteen patients were enrolled in the present study. RESULTS: Of the 13 patients, 11 experienced disease progression, 1 patient was withdrawn because of an adverse event (AE), and 1 patient died. Also, 11 patients (84.6%) experienced a treatment-emergent AE deemed related to P276-00. Of the 13 patients, 9 (69.2%) received >/= 2 cycles of treatment, which was the predefined threshold to be evaluable for efficacy. Treatment was discontinued early in 2 patients because of AEs (1 of which was attributed to P276-00 administration) and in 2 patients because of disease progression. Finally, 2 patients experienced stable disease for an estimated median duration of 60.5 days (range, 58-63 days). The estimated median time to progression for the predefined efficacy population was 43 days (range, 38-58 days). CONCLUSION: Given the results observed in the present study, if evaluation of CDK inhibition in MCL continues, it should be considered earlier in the disease course or as a part of combination strategies for relapsed or refractory disease.
Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma.[Pubmed:23414419]
J Transl Med. 2013 Feb 18;11:42.
BACKGROUND: Tumors of the head and neck present aggressive pathological behavior in patients due to high expression of CDK/CCND1 proteins. P276-00, a novel CDK inhibitor currently being tested in clinic, inhibits growth of several cancers in vitro and in vivo. The pre clinical activity of P276-00 in head and neck cancer and its potential mechanisms of action at molecular level are the focus of the current studies. METHOD: We have investigated the anti-cancer activity of P276-00 in head and neck tumors in vitro and in vivo. Candidate gene expression profiling and cell based proteomic approaches were taken to understand the pathways affected by P276-00 treatment. RESULTS: It was observed that P276-00 is cytotoxic across various HNSCC cell lines with an IC(5)(0) ranging from 1.0-1.5 mumoles/L and culminated in significant cell-cycle arrest in G1/S phase followed by apoptosis. P276-00 treatment suppressed cell proliferation through inhibition of CCND1 expression, reduced phosphorylation of retinoblastoma protein and abrogative transcription of E2F1 gene targets. Further, we observed that apoptosis was mediated through P53 activation leading to higher BAX/BCL-2 ratio and cleaved caspase-3 levels. It was also seen that P276-00 treatment reduced expression of tumor micro-environment proteins such as IL-6, secreted EGFR and HSPA8. Finally, P276-00 treatment resulted in significant tumor growth inhibition in xenograft tumor models via lowered proliferative activity of E2F1 and aggravated P53 mediated apoptosis. CONCLUSION: In summary, we have observed that P276-00 inhibits cyclin-D/CDK4/P16/pRB/E2F axis and induces apoptosis by increased P53 phosphorylation in HNSCC cells. These results suggest a novel indication for P276-00 in head and neck cancer with a potential role for IL-6 and HSPA8 as candidate serum biomarkers.
Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells.[Pubmed:23343191]
BMC Cancer. 2013 Jan 23;13:29.
BACKGROUND: In the present study, we show that the combination of doxorubicin with the cyclin-dependent kinase inhibitor P276-00 was synergistic at suboptimal doses in the non-small cell lung carcinoma (NSCLC) cell lines and induces extensive apoptosis than either drug alone in H-460 human NSCLC cells. METHODS: Synergistic effects of P276-00 and doxorubicin on growth inhibition was studied using the Propidium Iodide (PI) assay. The doses showing the best synergistic effect was determined and these doses were used for further mechanistic studies such as western blotting, cell cycle analysis and RT-PCR. The in vivo efficacy of the combination was evaluated using the H-460 xenograft model. RESULTS: The combination of 100 nM doxorubicin followed by 1200 nM P276-00 showed synergistic effect in the p53-positive and p53-mutated cell lines H-460 and H23 respectively as compared to the p53-null cell line H1299. Abrogation of doxorubicin-induced G2/M arrest and induction of apoptosis was observed in the combination treatment. This was associated with induction of tumor suppressor protein p53 and reduction of anti-apoptotic protein Bcl-2. Furthermore, doxorubicin alone greatly induced COX-2, a NF-kappaB target and Cdk-1, a target of P276-00, which was downregulated by P276-00 in the combination. Doxorubicin when combined with P276-00 in a sequence-specific manner significantly inhibited tumor growth, compared with either doxorubicin or P276-00 alone in H-460 xenograft model. CONCLUSION: These findings suggest that this combination may increase the therapeutic index over doxorubicin alone and reduce systemic toxicity of doxorubicin most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-kappaB signaling and inhibition of Cdk-1 which is involved in cell cycle progression.