LMK 235HDAC4/HDAC5 inhibitor CAS# 1418033-25-6 |
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Quality Control & MSDS
3D structure
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| Cas No. | 1418033-25-6 | SDF | Download SDF |
| PubChem ID | 71520717 | Appearance | Powder |
| Formula | C15H22N2O4 | M.Wt | 294.35 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 30 mg/mL (101.92 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | N-[6-(hydroxyamino)-6-oxohexoxy]-3,5-dimethylbenzamide | ||
| SMILES | CC1=CC(=CC(=C1)C(=O)NOCCCCCC(=O)NO)C | ||
| Standard InChIKey | VRYZCEONIWEUAV-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C15H22N2O4/c1-11-8-12(2)10-13(9-11)15(19)17-21-7-5-3-4-6-14(18)16-20/h8-10,20H,3-7H2,1-2H3,(H,16,18)(H,17,19) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Selective histone deacetylase (HDAC) 4 and HDAC5 inhibitor (IC50 values are 4.22, 11.9, 55.7, 320, 852, 881, and 1278 nM for HDAC 5, 4, 6, 1, 11, 2, and 8, respectively). Demonstrates activity against chemoresistant cancer cell lines in an MTT assay for cytotoxicity using human ovarian cancer cell lines A2780 and cisplatin resistant A2780CisR (IC50 = 0.49 and 0.32 μM respectively). |
LMK 235 Dilution Calculator
LMK 235 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 3.3973 mL | 16.9866 mL | 33.9732 mL | 67.9463 mL | 84.9329 mL |
| 5 mM | 0.6795 mL | 3.3973 mL | 6.7946 mL | 13.5893 mL | 16.9866 mL |
| 10 mM | 0.3397 mL | 1.6987 mL | 3.3973 mL | 6.7946 mL | 8.4933 mL |
| 50 mM | 0.0679 mL | 0.3397 mL | 0.6795 mL | 1.3589 mL | 1.6987 mL |
| 100 mM | 0.034 mL | 0.1699 mL | 0.3397 mL | 0.6795 mL | 0.8493 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Description:
IC50: cytotoxicity IC50 (490 nm for A2780; 320 nm for A2780 CisR); HDAC inhibition (650 nM for A2780; 320 nm for A2780 CisR)
Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, for example, valproic acid. In more recent times, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases.
In vitro: LMK235 showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. LMK235 shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range. In contrast to vorinostat, LMK235 showed a novel HDAC isoform selectivity profile with preference for HDAC4 and HDAC5, which are inhibited with low nanomolar IC50 values [1].
In vivo: In a mouse in-vivo study, synergistic inhibition was demonstrated for LMK235 and Cytarabine in proliferation assays and in colony formation assays. These findings demonstrate that in vivo RNAi screening for therapeutic efficacy is feasible. HDAC4 might be an important target to enhance efficacy of anti-leukemic drugs [2].
Clinical trial: LMK235 is currently in the preclinical development and no clinical trial is ongoing.
References:
[1] Marek L, Hamacher A, Hansen FK, Kuna K, Gohlke H, Kassack MU, Kurz T. Histone deacetylase (HDAC) inhibitors with a novel connecting unit linker region reveal a selectivity profile for HDAC4 and HDAC5 with improved activity against chemoresistant cancer cells. J Med Chem. 2013;56(2):427-36.
[2] Stephanie Lettermann, Konstantin Agelopoulos, Christian Rohde, Beate Lindtner, Linda Marek, Georg Hempel, Matthias Stelljes, Wolfgang E. Berdel, Thomas Kurz and Carsten Müller-Tidow. In Vivo RNAi Screening Identifies HDAC4 As a Mediator Of Chemoresistance In Acute Myeloid Leukemia. 55th ASH Annual Meeting and Exposition (2013) (https://ash.confex.com/ash/2013/webprogram/Paper60036.html)
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HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer.[Pubmed:27177225]
Oncotarget. 2016 Jun 21;7(25):37966-37978.
PURPOSE: Histone deacetylase 5 (HDAC5) is an important protein in neural and cardiac diseases and a potential drug target. However, little is known regarding the specific role of HDAC5 in breast cancer (BC). We aimed to evaluate HDAC5 expression in human breast tumors and to determine the effects of the inhibition of HDAC5 expression in BC cells. EXPERIMENTAL DESIGN: HDAC5 expression was evaluated in BC patients and was correlated with clinical features and with patient prognosis. Functional experiments were performed using shRNA and the selective HDAC inhibitor LMK-235 for HDAC5 knockdown and inhibition in BC cells. The synergistic effects of LMK-235 with the proteasome inhibitor bortezomib were also examined. RESULTS: HDAC5 was extensively expressed in human BC tissues, and high HDAC5 expression was associated with an inferior prognosis. Knockdown of HDAC5 inhibited cell proliferation, migration, invasion, and enhanced apoptosis. The HDAC5 inhibitor LMK-235 inhibited cell growth and induced apoptosis, while the inclusion of bortezomib synergistically enhanced the efficacy of LMK-235. CONCLUSIONS: Our findings indicate that HDAC5 is a promising prognostic marker and drug target for BC and that the combination of LMK-235 and bortezomib presents a novel therapeutic strategy for BC.
Histone deacetylase (HDAC) inhibitors with a novel connecting unit linker region reveal a selectivity profile for HDAC4 and HDAC5 with improved activity against chemoresistant cancer cells.[Pubmed:23252603]
J Med Chem. 2013 Jan 24;56(2):427-36.
The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described. Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound 19i (LMK235) (N-((6-(hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of 19i in comparison to vorinostat or trichostatin A (TSA). 19i shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range.
