Alvocidib

Alvocidib (INN; also known as Flavopiridol) is a flavonoid alkaloid CDK9 kinase inhibitor under clinical development for the treatment of acute myeloid leukemia, by Tolero Pharmaceuticals, Inc. It has been studied also for the treatment of arthritis[1] and atherosclerotic plaque formation[2] The target of Flavopiridol is the positive transcription elongation factor P-TEFb.[3][4] Treatment of cells with Flavopiridol leads to inhibition of P-TEFb and the loss of mRNA production.[5][6]

Alvocidib

Names
IUPAC name 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone
Other names Flavopiridol, HMR 1275, L-868275
Identifiers
CAS Number	146426-40-6
3D model (JSmol)	Interactive image
ChEBI	CHEBI:47344
ChEMBL	ChEMBL428690
ChemSpider	4450222
DrugBank	DB03496
IUPHAR/BPS	5680
KEGG	D09868
MeSH	Flavopiridol
PubChem CID	5287969
UNII	45AD6X575G
CompTox Dashboard (EPA)	DTXSID20904970
InChI 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 Key: BIIVYFLTOXDAOV-YVEFUNNKSA-N
SMILES Clc4ccccc4C=2Oc1c(c(O)cc(O)c1C(=O)C=2)[C@H]3CCN(C)C[C@H]3O
Properties
Chemical formula	C21H20ClNO5
Molar mass	401.8402
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

The compound is a synthetic analog of natural product rohitukine which was initially extracted from Amoora rohituka [syn. Aphanamixis polystachya] and later from Dysoxylum binectariferum.[7][8]

Orphan drug

Sumitomo Dainippon Pharma Oncology (formerly 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.[9]

References

1. Sekine C, Sugihara T, Miyake S, Hirai H, Yoshida M, Miyasaka N, Kohsaka H (2008). "Successful treatment of animal models of rheumatoid arthritis with small-molecule cyclin-dependent kinase inhibitors". J. Immunol. 180 (3): 1954–61. doi:10.4049/jimmunol.180.3.1954. PMID 18209094.
2. Ruef J, Meshel AS, Hu Z, Horaist C, Ballinger CA, Thompson LJ, Subbarao VD, Dumont JA, Patterson C (1999). "Flavopiridol inhibits smooth muscle cell proliferation in vitro and neointimal formation In vivo after carotid injury in the rat". Circulation. 100 (6): 659–65. doi:10.1161/01.cir.100.6.659. PMID 10441105.
3. Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA, Senderowicz AM, Peterlin BM, Price DH (2000). "Flavopiridol inhibits P-TEFb and blocks HIV-1 replication". J. Biol. Chem. 275 (37): 28345–8. doi:10.1074/jbc.C000446200. PMID 10906320.
4. Chao SH, Price DH (2001). "Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo". J. Biol. Chem. 276 (34): 31793–9. doi:10.1074/jbc.M102306200. PMID 11431468.
5. Cheng B, Li T, Rahl PB, Adamson TE, Loudas NB, Guo J, Varzavand K, Cooper JJ, Hu X, Gnatt A, Young RA, Price DH (2012). "Functional association of Gdown1 with RNA polymerase II poised on human genes". Mol. Cell. 45 (1): 38–50. doi:10.1016/j.molcel.2011.10.022. PMC 3259526. PMID 22244331.
6. Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, Sharp PA, Young RA (2010). "c-Myc regulates transcriptional pause release". Cell. 141 (3): 432–45. doi:10.1016/j.cell.2010.03.030. PMC 2864022. PMID 20434984.
7. Harmon, AD; Weiss, U; Silverton, JV (1979). "The structure of rohitukine, the main alkaloid of Amoora rohituka (syn.Aphanamixis polystachya) (Meliaceae)". Tetrahedron Lett. 20 (1): 721–724. doi:10.1016/S0040-4039(01)93556-7.
8. Lakdawala, AD; Shirole, MV; Mandrekar, SS; Dohadwalla, AN (1988). "Immunopharmacological potential of rohitukine: a novel compound isolated from the plant Dysoxylum binectariferum". Asia Pac J Pharmcol. 3 (1): 91–98.
9. http://www.healio.com/hematology-oncology/hematologic-malignancies/news/online/%7B74c6a69e-4529-400d-98e9-d5ee6c602122%7D/fda-grants-orphan-drug-status-to-alvocidib-for-aml