5.05763

ProRS Inhibitor, Halofuginone

• Synonym(s): ProRS Inhibitor, Halofuginone, STENOROL, HF, Hydrobromide, prolyl-tRNA synthetase Inhibitor, trans-(±)-7-Bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3H)-quinazolinone hydrobromide
• Empirical Formula (Hill Notation): C₁₆H₁₇BrClN₃O₃ · xHBr
• CAS Number: 64924-67-0
• Molecular Weight: 414.68 (free base basis)
• MDL number: MFCD23843776
• UNSPSC Code: 12352200
• NACRES: NA.77

Properties

• Assay: ≥98% (HPLC)
• Quality Level: 100
• form: powder
• potency: 18 nM IC₅₀
• manufacturer/tradename: Calbiochem^®
• storage condition: OK to freeze; protect from light
• color: white
• solubility: DMSO: 100 mg/mL
• storage temp.: 2-8°C
• InChI: 1S/C16H17BrClN3O3.BrH/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;1H/t14?,15-;/m1./s1
• InChI key: SJUWEPZBTXEUMU-NUNOUFIPSA-N

Description

General description

A cell-permeable racemic mixture of Halofuginone whose D-(+)/(2R, 3S) enantiomer serves as the active inhibitor against ProRS-mediated aminoacylation by simultaneously preventing ProRS-catalyzed Pro-AMP formation and the subsequent Pro transfer from Pro-AMP to tRNA^Pro. Proline, but not other NEAA, is able to reverse the inhibitory effect of HF in in vitro rabbit reticulocyte lysate translations (1 µM HF; 1 mM Pro) and prevent HF-induced cellular AAR pathway activation (100 nM HF/2 mM Pro/MEF; 10 nM HF/1 mM Pro/Murine CD4⁺ CD25^- T cells). Shown to inhibit bFGF-induced neovascularization in a murine corneal angiogenesis model (5 mg/kg/d via food intake) and significantly reduce the severity of MOG33-55-induced EAE in mice (2 µg/mouse/d i.p.) in vivo. Unlike AA-AMP mimetics, HF does not compete against ATP for ProRS binding.

A cell-permeable racemic mixture of Halofuginone, a halogenated derivative of the Dichroa febriguga alkaloid Febrifugine, whose D-(+)/(2R, 3S) enantiomer serves as the active inhibitor against ProRS- (prolyl-tRNA synthetase) mediated aminoacylation by simultaneously targeting/blocking ProRS Proline-binding pocket with its hydroxypiperidine and tRNA 3′ end adenosine-binding site with its halogenated 4-quinazolinone, preventing not only ProRS-catalyzed prolyl adenylation (Pro-AMP formation), but also the subsequent Pro transfer from Pro-AMP to tRNA^Pro. Consistently, only proline, but not other NEAA, is able to reverse the inhibitory effect of HF in in vitro rabbit reticulocyte lysate translations (1 µM HF; 1 mM Pro) and prevent HF-induced cellular AAR (amino acid response) pathway activation (100 nM HF/2 mM Pro/MEF; 10 nM HF/1 mM Pro/Murine CD4⁺ CD25^- T cells). Shown to inhibit bFGF-induced neovascularization in a murine corneal angiogenesis model (5 mg/kg/day via food intake) and significantly reduce the severity of myelin antigen MOG33-55-induced autoimmune EAE/encephalomyelitis in mice (2 µg/mouse/day i.p.) in vivo. Unlike AA-AMP mimetics, HF does not compete against ATP for ProRS binding. ATP, in its ProRS bound state, actually helps stabilize HF via hydrogen bond interactions.

Biochem/physiol Actions

Primary Target
prolyl-tRNA synthetase

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

Other Notes

Zhou, H., et al. 2013, Nature494, 121.

Keller, T.L., et al. 2012, Nat. Chem. Biol.12, 311.

Sundrud, M.S., et al. 2009, Science324, 1334.
Elkin, M., et al. 2000, FASEB J.14, 2477.
Elkin, M., et al. 1999, Clin. Cancer Res.5, 1982.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Safety Information

• Pictograms: GHS06,GHS09
• Signal Word: Danger
• Hazard Statements: H300 + H310 + H330 - H315 - H319 - H410
• Precautionary Statements: P262 - P264 - P273 - P280 - P302 + P352 + P310 - P304 + P340 + P310
• Hazard Classifications: Acute Tox. 1 Dermal - Acute Tox. 2 Inhalation - Acute Tox. 2 Oral - Aquatic Acute 1 - Aquatic Chronic 1 - Eye Irrit. 2 - Skin Irrit. 2
• Storage Class Code: 6.1A - Combustible, acute toxic Cat. 1 and 2 / very toxic hazardous materials
• WGK: WGK 3
• Flash Point(F): Not applicable
• Flash Point(C): Not applicable