Halofuginone

Halofuginone
Clinical data
AHFS/Drugs.com	International Drug Names
ATCvet code	QP51AX08 (WHO) ;
Identifiers
	IUPAC name 7-Bromo-6-chloro-3-[3-[(2S,3R)-3-hydroxy-2-piperidinyl]-2-oxopropyl]-4-quinazolinone;
CAS Number	55837-20-2 ;
PubChem CID	400772;
ChemSpider	355164 ;
UNII	L31MM1385E;
ChEMBL	ChEMBL1199540 ;
CompTox Dashboard (EPA)	DTXSID0048260 ;
Chemical and physical data
Formula	C16H17BrClN3O3
Molar mass	414.68 g/mol g·mol−1
3D model (JSmol)	Interactive image; Interactive image;
	SMILES O=C(CN3C=NC2=CC(Br)=C(Cl)C=C2C3=O)C[C@@H]1NCCC[C@H]1O; ; Brc1cc2/N=C\N(C(=O)c2cc1Cl)CC(=O)C[C@@H]3NCCC[C@H]3O;
	InChI InChI=1S/C16H17BrClN3O3/c17-11-6-13-10(5-12(11)18)16(24)21(8-20-13)7-9(22)4-14-15(23)2-1-3-19-14/h5-6,8,14-15,19,23H,1-4,7H2/t14-,15+/m0/s1 ; Key:LVASCWIMLIKXLA-LSDHHAIUSA-N ;
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Halofuginone is a coccidiostat used in veterinary medicine. It is a synthetic halogenated derivative of febrifugine, a natural quinazolinone alkaloid which can be found in the Chinese herb Dichroa febrifuga (Chang Shan).^[1] Collgard Biopharmaceuticals is developing halofuginone for the treatment of scleroderma and it has received orphan drug designation from the U.S. Food and Drug Administration.^[2]

Halofuginone inhibits the development of T helper 17 cells, immune cells that play an important role in autoimmune disease, but it does not affect other kinds of T cells which are involved in normal immune function.^[3] Halofuginone therefore has potential for the treatment of autoimmune disorders.^[4]

Halofuginone is also an inhibitor of collagen type I gene expression and as a consequence it may inhibit tumor cell growth.^[1] Halofuginone exerts its effects by acting as a high affinity inhibitor of the enzyme Glutamyl-Prolyl tRNA synthetase. Inhibition of prolyl tRNA charging leads to the accumulation of uncharged prolyl tRNAs, which serve as a signal to initiate the amino acid starvation response, which in turn exerts anti-inflammatory and anti-fibrotic effects.^[5]

References

^ ^a ^b Halofuginone hydrobromide, NCI Drug Dictionary
^ Halofuginone Receives FDA Orphan Drug Status For Scleroderma, March 10, 2000
^ Sundrud, M. S.; Koralov, S. B.; Feuerer, M.; Calado, D. P.; Kozhaya, A. E.; Rhule-Smith, A.; Lefebvre, R. E.; Unutmaz, D.; Mazitschek, R. (2009). "Halofuginone Inhibits TH17 Cell Differentiation by Activating the Amino Acid Starvation Response". Science. 324 (5932): 1334–8. doi:10.1126/science.1172638. PMC 2803727. PMID 19498172.
^ A new lead for autoimmune disease: A small-molecule drug inhibits Th17 cells, eases symptoms in mouse model, June 4, 2009
^ Keller et al (2012) Halofuginone and other febrifugine derivatives inhibit prolyl-trna synthetase. Nature Chemical Biology 12;8(3):311-7. doi: 10.1038/nchembio.790.

[drugdictionary-1] Halofuginone hydrobromide, NCI Drug Dictionary

[2] Halofuginone Receives FDA Orphan Drug Status For Scleroderma, March 10, 2000

[3] Sundrud, M. S.; Koralov, S. B.; Feuerer, M.; Calado, D. P.; Kozhaya, A. E.; Rhule-Smith, A.; Lefebvre, R. E.; Unutmaz, D.; Mazitschek, R. (2009). "Halofuginone Inhibits TH17 Cell Differentiation by Activating the Amino Acid Starvation Response". Science. 324 (5932): 1334–8. doi:10.1126/science.1172638. PMC 2803727. PMID 19498172.

[4] A new lead for autoimmune disease: A small-molecule drug inhibits Th17 cells, eases symptoms in mouse model, June 4, 2009

[5] Keller et al (2012) Halofuginone and other febrifugine derivatives inhibit prolyl-trna synthetase. Nature Chemical Biology 12;8(3):311-7. doi: 10.1038/nchembio.790.

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