Description
Panobinostat is a potent inhibitor of all histone deacetylases (HDACs), with K
i values ranging from 0.6 to 31 nM for HDAC1-
11. Through this action, it leads to acetylation of a range of cellular proteins, resulting in cell cycle arrest and apoptosis in cancer cells. It has potential applications in several different forms of cancer as well as in spinal muscular atrophy and HIV therapy.
Chemical Properties
Yellow Solid
Uses
The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells.
Uses
The novel labelled histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells.
Definition
ChEBI: A hydroxamic acid obtained by formal condensation of the carboxy group of (2E)-3-[4-({[2-(2-methylindol-3-yl)ethyl]amino}methyl)phenyl]prop-2-enoic acid with the amino group of hydroxylamine. A histone deacetylase inhibitor used (as its la
tate salt) in combination with bortezomib and dexamethasone for the treatment of multiple myeloma.
Clinical Use
Histone deacetylase (HDAC) inhibitor:
Treatment of relapsed and/or refractory multiple
myeloma
Synthesis
To a 250 mL four-necked flask was added (E)-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylic acid methyl ester hydrochloride (15 g, 0.039 mol) and methanol (75 mL) and cooled with stirring to -10°C to 15°C. Sodium hydroxide (4.68 g, 0.117 mol) was added rapidly to the methanol solution and stirred for 10 minutes after dropwise addition. Hydroxylamine solution (32.52 g, 50% aqueous solution, equivalent to 16.26 g, 0.234 mol of hydroxylamine hydrochloride) was then added dropwise and the reaction was stirred for 2 hrs keeping the temperature at -10°C to 15°C. The reaction mixture was slowly warmed up to -10°C to 15°C. The reaction mixture was then stirred for 10 min. The reaction mixture was slowly warmed to 0°C, held at 0-5°C for 30 minutes, then continued to warm to 20°C, held at 20-25°C for 1 hour. 38 mL of water was added dropwise, stirred for 10 minutes and filtered, and the filter cake was washed with 38 mL of water. The pH of the filtrate was adjusted to 10 with aqueous hydrochloric acid (~18.5 g of 2 mol/L aqueous solution). the crystals were stirred at 20-25°C and the pH was continued to 8-9 with hydrochloric acid (~15.5 g of 2 mol/L aqueous solution) and kept stirring at 20-25°C for 1 hour. The solution pH was further adjusted to 3-4 and the solid was filtered after stirring for 1 hour. The filter cake was rinsed with 50 mL of methanol-water mixture (v/v = 1:1) and dried to constant weight in a hot air oven at 50°C to afford the target product (E)-N-hydroxy-3-(4-(((2-(2-methyl-1H-indol-3-yl)ethyl)amino)methyl)phenyl)acrylamide 12.89 g in 94.6% yield.
target
HDAC (MOLT-4 cells)
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: avoid with dextromethorphan possibly
increased risk of ventricular arrhythmias with
methadone - avoid.
Anti-arrhythmics: increased risk of ventricular
arrhythmias with amiodarone and possibly
disopyramide - avoid.
Antibacterials: increased risk of ventricular
arrhythmias with clarithromycin and moxifloxacin -
avoid; avoid with rifampicin.
Antidepressants: avoid with St John’s wort.
Antiepileptics: avoid with carbamazepine,
fosphenytoin, phenobarbital, phenytoin and
primidone.
Antifungals: concentration increased by ketoconazole
and possibly posaconazole and voriconazole - reduce
panobinostat dose; concentration possibly increased
by itraconazole - avoid.
Antimalarials: possibly increased risk of ventricular
arrhythmias with chloroquine - avoid.
Antipsychotics: avoid with pimozide.
Antivirals: concentration possibly increased
by ritonavir and saquinavir - reduce dose of
panobinostat.
Beta-blockers: possibly increased risk of ventricular
arrhythmias with sotalol - avoid.
Grapefruit juice: avoid concomitant use.
5HT3
antagonists: possibly increased risk of
ventricular arrhythmias with granisetron and
ondansetron - avoid with granisetron.
Metabolism
Panobinostat is extensively metabolised, and a large
fraction of the dose is metabolised before reaching
the systemic circulation by reduction, hydrolysis,
oxidation and glucuronidation. Oxidative metabolism
of panobinostat played a less prominent role, with
approximately 40% of the dose eliminated by this
pathway. Cytochrome P450 3A4 (CYP3A4) is the main
oxidation enzyme, with potential minor involvement of
CYP2D6 and 2C19.
Panobinostat represented 6-9% of the drug-related
exposure in plasma. The parent substance is deemed to
be responsible for the overall pharmacological activity of
panobinostat.
After a single oral dose of [14C]-panobinostat in patients,
29-51% of administered radioactivity is excreted in the
urine and 44-77% in the faeces. Unchanged panobinostat
accounted for <2.5% of the dose in urine and <3.5% of
the dose in faeces.
References
[1] LING GENG. Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer.[J]. Cancer research, 2006, 66 23: 11298-11304. DOI:
10.1158/0008-5472.can-06-0049[2] PRINCE GEORGE. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3.[J]. Blood, 2005, 105 4: 1768-1776. DOI:
10.1182/blood-2004-09-3413[3] PATRICIA MAISO. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance.[J]. Cancer research, 2006, 66 11: 5781-5789. DOI:
10.1158/0008-5472.can-05-4186
