HDAC; HIV-1

LBH589 significantly reduces tumor growth in animal models of mesothelioma and lung cancer by 62%. Immunocompetent and severely combined immunodeficient mice respond to LBH589 just as well, indicating that LBH589's ability to inhibit tumor growth is not a result of direct immunologic effects. LBH589 was administered intraperitoneally five days a week at a dose of 20 mg/kg, resulting in a 70% reduction in growth on average. LBH589 causes a 53% decrease for H526-derived tumors, an 81% decrease for BK-T-derived tumors, a 76% decrease for RG-1-derived tumors, and a 70% decrease for H69-derived tumors when compared to the corresponding control tumors. LBH589 causes a significant tumor regression in tumors derived from SCLC and RG-1, in contrast to the absence of tumor regression notes in NSCLC and Meso-derived xenografted tumors that are treated under the same circumstances and doses. [2]

Panobinostat is a non-selective histone deacetylase (HDAC) inhibitor.

The annexin V-FITC apoptosis detection kit is used to stain both untreated and LBH589-treated human Ph- acute lymphoblastic leukemia MOLT-4 (T cells) and Reh (pre-B cells) cells. Me. Flow cytometry is used to calculate the percentage of nonviable and apoptotic cells. Using a CyAn ADP Violet cytometer, a minimum of 5 × 10⁴ cells are obtained. The percentages of apoptosis and cell viability are determined by adding together all annexin V-positive, PI-positive, and annexin V/PI-positive cells.Furthermore, percentages of cell viability are calculated by adding together all annexin V-positive, PI-positive, and annexin V/PI-positive cells.

Absorption, Distribution and Excretion
After a 20 mg dose, panobinostat was quickly absorbed with a time to maximum absorption of 2 hours.

---

Metabolism / Metabolites
Panobinostat was extensively metabolized to 77 metabolites. Unchanged panobinostat recovered in urine and feces was 2% and 3%, respectively. Primary metabolic pathways of panobinostat are reduction, hydrolysis, oxidation, and glucuronidation processes. CYP and non-CYP enzymes were found to play significant role in metabolism, CYP2D6 and CYP2C19 playing minor roles.

---

Biological Half-Life
30 hours

Hepatotoxicity
Most clinical trials of panobinostat have not reported rates of serum enzyme elevations during therapy and it is typically given in combination with other antineoplastic agents that can cause serum ALT and AST elevations. In the large controlled trial of panobinostat vs placebo in combination with bortezomib and dexamethasone, ALT elevations occurred in similar proportion of patients receiving panobinostat (31%) as placebo (38%) and values above 5 times the upper limit of normal were uncommon (1.8% and 1.3%). In addition, there have been no reports of clinically apparent liver injury with jaundice associated with panobinostat therapy. Thus, panobinostat appears to have little hepatotoxic potential and liver injury from panobinostat must be quite rare, if it occurs at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

[1]. Blood . 2008 May 15;111(10):5093-100.

[2]. Mol Cancer Ther . 2009 Aug;8(8):2221-31.

[3]. Haematologica . 2010 May;95(5):794-803.

[4]. Cancer Res . 2006 Jun 1;66(11):5781-9.

[5]. Cancer Lett . 2009 Aug 8;280(2):233-41.

Panobinostat is 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 lactate salt) in combination with bortezomib and dexamethasone for the treatment of multiple myeloma. It has a role as an EC 3.5.1.98 (histone deacetylase) inhibitor, an antineoplastic agent and an angiogenesis modulating agent. It is a hydroxamic acid, a member of cinnamamides, a secondary amino compound and a methylindole. It is a conjugate base of a panobinostat(1+).
Panobinostat is a drug that was previously approved by the U.S. Food and Drug Administration (FDA) under the brand name Farydak for the treatment of a certain type of cancer. Panobinostat is currently being studied as an investigational drug as part of a strategy to cure HIV infection. As an investigational HIV therapy, panobinostat belongs to a group of drugs called latency-reversing agents.
Panobinostat is an oral deacetylace (DAC) inhibitor approved on February 23, 2015 by the FDA for the treatment of multiple myeloma. The approval was accelerated based on progression-free survival, therefore confirmatory trials by the sponsor to demonstrate clinical efficacy in multiple myeloma treatment are in progress of being conducted. Panobinostat is marketed by Novartis under the brand name Farydak. Panobinostat acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor) and it is the most potent DAC inhibiting agent available on the market.
Histone deacetylase (hdac) inhibitor is a Histone Deacetylase Inhibitor. The mechanism of action of histone deacetylase (hdac) inhibitor is as a Histone Deacetylase Inhibitor, and Cytochrome P450 2D6 Inhibitor.
Panobinostat is an oral histone deacetylase inhibitor and antineoplastic agent that is approved for use in combination with other agents in refractory or relapsed multiple myeloma. Panobinostat is associated with modest rate of minor serum enzyme elevations during therapy, but has not been linked to cases of clinically apparent liver injury.
Panobinostat is a cinnamic hydroxamic acid analogue with potential antineoplastic activity. Panobinostat selectively inhibits histone deacetylase (HDAC), inducing hyperacetylation of core histone proteins, which may result in modulation of cell cycle protein expression, cell cycle arrest in the G2/M phase and apoptosis. In addition, this agent appears to modulate the expression of angiogenesis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1a) and vascular endothelial growth factor (VEGF), thus impairing endothelial cell chemotaxis and invasion. HDAC is an enzyme that deacetylates chromatin histone proteins.
An indole and hydroxamic acid derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used as an antineoplastic agent in combination with BORTEZOMIB and DEXAMETHASONE for the treatment of MULTIPLE MYELOMA.
See also: Panobinostat Lactate (active moiety of).

---

Drug Indication
Panobinostat is indicated in the treatment of multiple myeloma in combination with dexamethasone and bortezomib in patients who have received 2 previous treatment regimens including bortezomib and an immunomodulatory agent. This indication is approved by accelerated approval based on progression free survival as of February 23, 2015.
FDA Label
Farydak, in combination with bortezomib and dexamethasone, is indicated for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent. Farydak, in combination with bortezomib and dexamethasone, is indicated for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent.

---

Mechanism of Action
Panobinostat is a deacetylase (DAC) inhibitor. DACs, also known as histone DACs (HDAC), are responsible for regulating the acetylation of about 1750 proteins in the body; their functions are involved in many biological processes including DNA replication and repair, chromatin remodelling, transcription of genes, progression of the cell-cycle, protein degradation and cytoskeletal reorganization. In multiple myeloma, there is an overexpression of DAC proteins. Panobinostat inhibits class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10) and class IV (HDAC 11) proteins. Panobinostat's antitumor activity is believed to be attributed to epigenetic modulation of gene expression and inhibition of protein metabolism. Panobinostat also exhibits cytotoxic synergy with bortezomib, a proteasome inhibitor concurrently used in treatment of multiple myeloma.

C21H23N3O2

349.43

349.179

C, 72.18; H, 6.63; N, 12.03; O, 9.16

404950-80-7

404950-80-7;960055-56-5 (lactate); 960055-60-1 (mesylate);960055-50-9 (acetate); 960055-54-3 (fumarate); 960055-57-6

6918837

White to off-white solid powder

1.2±0.1 g/cm3

114-117?C

1.683

3.62

4

3

7

26

474

0

O=C(/C(/[H])=C(\[H])/C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])N([H])C([H])([H])C([H])([H])C1=C(C([H])([H])[H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)N([H])O[H]

FPOHNWQLNRZRFC-ZHACJKMWSA-N

InChI=1S/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+

(E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide

NVP-LBH589; NVP-LBH 589; LBH589; LBH 589; LBH-589; Panobinostat; Brand name Farydak

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (7.15 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (7.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: ≥ 2.5 mg/mL (7.15 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 5: 2.5 mg/mL (7.15 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

Solubility in Formulation 6: 2% DMSO+48% PEG 300+2% Tween 80+ddH2O: 5mg/mL

---

 (Please use freshly prepared in vivo formulations for optimal results.)