Alvocidib Explained

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

The compound is a synthetic analog of natural product rohitukine which was initially extracted from Aphanamixis polystachya (formerly Amoora rohituka, hence the name) and later from Dysoxylum binectariferum.^{[7] [8]}

Orphan drug

The FDA has granted orphan drug designation to alvocidib for the treatment of patients with acute myeloid leukemia.^[9]

Notes and References

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