Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C21H20ClNO5 |
Molecular Weight | 401.84 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1CC[C@@H]([C@H](O)C1)C2=C(O)C=C(O)C3=C2OC(=CC3=O)C4=C(Cl)C=CC=C4
InChI
InChIKey=BIIVYFLTOXDAOV-YVEFUNNKSA-N
InChI=1S/C21H20ClNO5/c1-23-7-6-12(17(27)10-23)19-14(24)8-15(25)20-16(26)9-18(28-21(19)20)11-4-2-3-5-13(11)22/h2-5,8-9,12,17,24-25,27H,6-7,10H2,1H3/t12-,17+/m0/s1
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/27118540Curator's Comment: The description was created based on several sources, including
https://clinicaltrials.gov/ct2/show/NCT00020332 | https://clinicaltrials.gov/ct2/show/NCT00020189 | https://clinicaltrials.gov/ct2/show/NCT00464633 | https://clinicaltrials.gov/ct2/show/NCT00445341
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27118540
Curator's Comment: The description was created based on several sources, including
https://clinicaltrials.gov/ct2/show/NCT00020332 | https://clinicaltrials.gov/ct2/show/NCT00020189 | https://clinicaltrials.gov/ct2/show/NCT00464633 | https://clinicaltrials.gov/ct2/show/NCT00445341
Alvocidib (also known as Flavopiridol or HMR-1275) is a flavonoid alkaloid CDK9 kinase inhibitor under clinical development for the treatment of acute myeloid leukemia, by Tolero Pharmaceuticals, Inc. As a broad spectrum CDK inhibitor, Alvocidib can inhibit cell cycle progression in either G1 or G2 and induces G1 arrest in either MCF-7 or MDA-MB-468 cells by inhibition of the CDK4 or CDK2 kinase activity. Alvocidib exhibits potent cytotoxicity against a wide variety of tumor cell lines (LNCAP, HCT116, A2780, K562, PC3, and Mia PaCa-2) with IC50 values ranging from 16 nM for LNCAP to 130 nM for K562. Administration of Alvocidib at 7.5 mg/kg for 7 days displays slight antitumor activity against P388 murine leukemia, and active against the human A2780 ovarian carcinoma implanted sc in nude mice). Alvocidib treatment at 1-2.5 mg/kg for 10 days significantly suppresses collagen-induced arthritis in mice in a dose-dependent manner, by inhibiting synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII are maintained. Tolero Pharmaceuticals Inc. announced that the FDA has granted orphan drug designation for Alvocidib, its cyclin-dependent kinase small molecule inhibitor, for the treatment of patients with acute myeloid leukemia.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL331 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22037378 |
3.3 nM [Kd] | ||
Target ID: CHEMBL3116 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23252711 |
3.0 nM [Ki] | ||
Target ID: CHEMBL1163112 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22037378 |
7.1 nM [Kd] | ||
Target ID: CHEMBL1163126 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22037378 |
0.69 nM [Kd] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
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OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
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yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
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major [Km 37 uM] | ||||
minor | ||||
minor | ||||
minor | ||||
minor | ||||
minor | ||||
minor | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
yes [Km 175 uM] | ||||
yes [Km 66 uM] | ||||
yes [Km 66.8 uM] | ||||
yes | ||||
yes |
PubMed
Title | Date | PubMed |
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[CDK inhibitors for therapy of cancer]. | 2001 Apr |
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In vitro glucuronidation of the cyclin-dependent kinase inhibitor flavopiridol by rat and human liver microsomes: involvement of UDP-glucuronosyltransferases 1A1 and 1A9. | 2001 Apr |
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Flavopiridol. National Cancer Institute. | 2001 Aug |
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Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies. | 2001 Jan |
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Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? | 2001 Jan 5 |
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Treatment with inhibitors of caspases, that are substrates of drug transporters, selectively permits chemotherapy-induced apoptosis in multidrug-resistant cells but protects normal cells. | 2001 Jun |
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A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. | 2001 Jun |
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Characterization of the Trypanosoma cruzi Cdc2p-related protein kinase 1 and identification of three novel associating cyclins. | 2001 Mar |
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Early development of cyclin dependent kinase modulators. | 2001 Nov |
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Cytotoxic agents in the era of molecular targets and genomics. | 2002 |
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The cell cycle as a target for cancer therapy: basic and clinical findings with the small molecule inhibitors flavopiridol and UCN-01. | 2002 |
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Finding the needle in the haystack: why high-throughput screening is good for your health. | 2002 |
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Rate-limiting effects of Cyclin D1 in transformation by ErbB2 predicts synergy between herceptin and flavopiridol. | 2002 Apr 15 |
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Pharmacological treatments for prostate cancer. | 2002 Dec |
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Inhibition of cyclin-dependent kinases improves CA1 neuronal survival and behavioral performance after global ischemia in the rat. | 2002 Feb |
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Extracellular nucleotides inhibit growth of human oesophageal cancer cells via P2Y(2)-receptors. | 2002 Feb 12 |
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Review of flavopiridol, a cyclin-dependent kinase inhibitor, as breast cancer therapy. | 2002 Jun |
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Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol. | 2002 Mar |
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Selective sensitization of transformed cells to flavopiridol-induced apoptosis following recruitment to S-phase. | 2002 Mar 15 |
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New anti-HIV agents and targets. | 2002 Nov |
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Conversion of drug-induced differentiation to apoptosis by pharmacologic cyclin-dependent kinase inhibitors. | 2002 Nov-Dec |
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Signal transduction--directed cancer treatments. | 2003 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT00464633
30 mg/m2 as a 30-minute intravenous (IV) infusion followed by 30 mg/m2 as a 4-hour continuous infusion. Cycles with 4-week treatment with alvocidib followed by 2-week rest period for up to a maximum of 6 cycles
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24084453
Skov-3 and BG-1 human ovarian cancer cells were used for activity evaluation. Cells (104/ml) were distributed into 96 well plates (“Greiner”, Frickenhausen, Germany) and allowed to adhere for 24 h. Medium was replaced by fresh medium containing vehicle or treatment reagents (Alvocidib 0.01, 0.1, 1, 10 ,100, 100 nM). After the indicated treatment period, cells were fixed by adding 10% glutamatealdehyde (“Merck”, Darmstadt, Germany) solution and stained by 0.05% crystal violet (“Sigma”) in 25% methanol. Following washing three times with double distilled water, cell bound crystal violet was dissolved in 0.1 M sodium citrate and measured at 560 nm (“ELISA Reader, Tecan”, Grödig, Austria). Experiments repeated in triplicate.
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
239607
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EU-Orphan Drug |
EU/3/15/1437
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FDA ORPHAN DRUG |
426214
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NCI_THESAURUS |
C2185
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5287969
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90998
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ALVOCIDIB
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47344
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SUB22877
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DB03496
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C74940
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XX-93
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C077990
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100000086877
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45AD6X575G
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CHEMBL428690
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m5396
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146426-40-6
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DTXSID20904970
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ACTIVE MOIETY
PRODRUG (METABOLITE ACTIVE)
SALT/SOLVATE (PARENT)