404950-80-7 Usage
Description
Panobinostat is a potent inhibitor of all histone deacetylases (HDACs), with Ki 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
Different sources of media describe the Uses of 404950-80-7 differently. You can refer to the following data:
1. The novel labelled histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells.
2. The novel 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
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) Geng et al. (2006), Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer; Cancer Res., 66 11298
2) George et al. (2005), 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; Blood, 105 1768
3) Maiso et al. (2006), The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance; Cancer Res., 66 5781
Check Digit Verification of cas no
The CAS Registry Mumber 404950-80-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,0,4,9,5 and 0 respectively; the second part has 2 digits, 8 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 404950-80:
(8*4)+(7*0)+(6*4)+(5*9)+(4*5)+(3*0)+(2*8)+(1*0)=137
137 % 10 = 7
So 404950-80-7 is a valid CAS Registry Number.
InChI:InChI=1/C21H23N3O2/c1-15-18(19-4-2-3-5-20(19)23-15)12-13-22-14-17-8-6-16(7-9-17)10-11-21(25)24-26/h2-11,22-23,26H,12-14H2,1H3,(H,24,25)/b11-10+
404950-80-7Relevant articles and documents
PROCESS FOR THE PREPARATION OF PANOBINOSTAT
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Page/Page column 13-14, (2021/09/03)
The present invention relates to a new process for the preparation of Panobinostat and intermediates thereof.
Zap-Pano: a Photocaged Prodrug of the KDAC Inhibitor Panobinostat
Troelsen, Kathrin S.,Calder, Ewen D. D.,Skwarska, Anna,Sneddon, Deborah,Hammond, Ester M.,Conway, Stuart J.
, p. 3691 - 3700 (2021/08/09)
We report the synthesis and biological evaluation of a light-activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap-Pano). We demonstrate that addition of the 4,5-dimethoxy-2-nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap-Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap-Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.
Panobinostat intermediate as well as synthesis and application thereof
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Paragraph 0062-0064, (2018/12/02)
The invention belongs to the field of medicine synthesis and in particular relates to a panobinostat intermediate as well as synthesis and application thereof. The intermediate is shown as a formula II and is obtained by taking 2-methyltryptamine and 4-chloromethylbenzaldehyde to react; raw materials are cheap and easy to obtain, reaction conditions are moderate and the operation is simple; the intermediate is used as a raw material to prepare panobinostat, the cost is low, reaction steps are few, the purity is high, the reaction conditions are moderate and the operation is simple; the qualitycontrol and cost reduction of panobinostat crude drugs are facilitated. (The formula II is shown in the description.).
