LDN-57444 | CAS#668467-91-2 | proteasome inhibitor| MedKoo Biosciences

MedKoo Cat#: 510324 | Name: LDN-57444

Description:

WARNING: This product is for research use only, not for human or veterinary use.

LDN-57444 is a Uch-L1 inhibitor ( ubiquitin C-terminal hydrolase-L1) with Ki= 0.4 μ M. Ubiquitin carboxy-terminal hydrolase L1 ( UCH-L1 ) is an intracellular protein abundantly expressed in neurons, and a mutation in UCH-L1 has been identified in familial Parkinson's disease.

Chemical Structure

LDN-57444

CAS#668467-91-2

Theoretical Analysis

MedKoo Cat#: 510324

Name: LDN-57444

CAS#: 668467-91-2

Chemical Formula: C17H11Cl3N2O3

Exact Mass: 395.9835

Molecular Weight: 397.64

Elemental Analysis: C, 51.35; H, 2.79; Cl, 26.75; N, 7.04; O, 12.07

Price and Availability

Size	Price	Availability
10mg	USD 110.00	Ready to ship
25mg	USD 220.00	Ready to ship
50mg	USD 385.00	Ready to ship
100mg	USD 650.00	Ready to ship
250mg	USD 1,250.00	Ready to ship

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Related CAS #

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Synonym

LDN57444; LDN 57444; LDN-57444.

IUPAC/Chemical Name

(Z)-3-(acetoxyimino)-5-chloro-1-(2,5-dichlorobenzyl)indolin-2-one.

InChi Key

OPQRFPHLZZPCCH-PGMHBOJBSA-N

InChi Code

InChI=1S/C17H11Cl3N2O3/c1-9(23)25-21-16-13-7-12(19)3-5-15(13)22(17(16)24)8-10-6-11(18)2-4-14(10)20/h2-7H,8H2,1H3/b21-16-

SMILES Code

O=C1N(CC2=CC(Cl)=CC=C2Cl)C3=C(C=C(Cl)C=C3)/C1=N/OC(C)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#CRB50928

QC Data

View QC data: current batch, Lot#CRB50928

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

LDN-57444 is an inhibitor of ubiquitin C-terminal hydrolase L1 (UCH-L1), with an IC50 of 0.88 μM and a Ki of 0.40 μM; LDN-57444 also suppresses UCH-L3 activity, with an IC50 of 25 μM.

In vitro activity:

Initially, this study tested two forms of LDN inhibitor of UCH-L1 DUB activity on the viability and migration of the well-established nasopharyngeal NP69 parental control line, and on the NP69 cell line stably expressing EBV pro-metastatic factor, LMP1 (Figure 3). Figure 3A demonstrates a visible boost in UCH-L1 expression levels in LMP1 stably-expressing NP69 cell line.. The results of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay in Figure 3B show that in concentration higher than 5 μM both forms of inhibitor start inducing death in both NP69 and NP69-LMP1 cells definitely through non-specific, UCH-L1-independent pathways. Reference: Int J Mol Sci. 2019 Aug; 20(15): 3733. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696221/

In vivo activity:

LDN57444-treated SHRs (spontaneously hypertensive rats) showed significantly reduced systolic blood pressure, although the inhibitor did not normalize the hypertension to the level observed in WKY rats (P < 0.05) (Figure 2b). H&E staining showed that the ganglion cell layer was loose and swollen. The thickness of the central retina (at two optic-disc diameters from the optic disc), particularly the inner plexiform, inner nuclear, and photoreceptor layers, was markedly increased in SHRs. These elevations were significantly reduced in LDN57444-treated SHRs (P < 0.05) (Figure 2c). However, the peripheral retinal morphology and thickness in the 4 groups were similar (Figure 2d). The accumulation of ionized calcium-binding adaptor molecule 1-positive microglia/macrophages was observed in vehicle-treated SHRs; this accumulation was significantly attenuated in LDN57444-treated SHRs (P < 0.05) (Figure 2e). These results suggest that LDN57444 treatment attenuates hypertension and hypertensive retinopathy in SHRs. Reference: J Int Med Res. 2021 Jun; 49(6): 03000605211020641. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212382/

	Solvent	mg/mL	mM
Solubility
	DMSO	14.7	37.02
	DMF	16.0	40.24
	DMF:PBS (pH 7.2) (1:2)	0.3	0.75

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 397.64 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Kobayashi E, Hwang D, Bheda-Malge A, Whitehurst CB, Kabanov AV, Kondo S, Aga M, Yoshizaki T, Pagano JS, Sokolsky M, Shakelford J. Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells. Int J Mol Sci. 2019 Jul 31;20(15):3733. doi: 10.3390/ijms20153733. PMID: 31370144; PMCID: PMC6696221. 2. Tan YY, Zhou HY, Wang ZQ, Chen SD. Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor. Mol Cell Biochem. 2008 Nov;318(1-2):109-15. doi: 10.1007/s11010-008-9862-x. Epub 2008 Jul 12. PMID: 18622688. 3. Liu S, Wang C, Lu J, Dai G, Che H, He W. Long-term inhibition of UCHL1 decreases hypertension and retinopathy in spontaneously hypertensive rats. J Int Med Res. 2021 Jun;49(6):3000605211020641. doi: 10.1177/03000605211020641. PMID: 34130526; PMCID: PMC8212382. 4. Gong Z, Ye Q, Wu JW, Zhou JL, Kong XY, Ma LK. UCHL1 inhibition attenuates cardiac fibrosis via modulation of nuclear factor-κB signaling in fibroblasts. Eur J Pharmacol. 2021 Jun 5;900:174045. doi: 10.1016/j.ejphar.2021.174045. Epub 2021 Mar 19. PMID: 33745956.

In vitro protocol:

In vivo protocol:

1. Liu S, Wang C, Lu J, Dai G, Che H, He W. Long-term inhibition of UCHL1 decreases hypertension and retinopathy in spontaneously hypertensive rats. J Int Med Res. 2021 Jun;49(6):3000605211020641. doi: 10.1177/03000605211020641. PMID: 34130526; PMCID: PMC8212382. 2. Gong Z, Ye Q, Wu JW, Zhou JL, Kong XY, Ma LK. UCHL1 inhibition attenuates cardiac fibrosis via modulation of nuclear factor-κB signaling in fibroblasts. Eur J Pharmacol. 2021 Jun 5;900:174045. doi: 10.1016/j.ejphar.2021.174045. Epub 2021 Mar 19. PMID: 33745956.

1: Sankiewicz A, Laudanski P, Romanowicz L, Hermanowicz A, Roszkowska-Jakimiec W, Debek W, Gorodkiewicz E. Development of surface plasmon resonance imaging biosensors for detection of ubiquitin carboxyl-terminal hydrolase L1. Anal Biochem. 2015 Jan 15;469:4-11. doi: 10.1016/j.ab.2014.09.021. Epub 2014 Oct 13. PubMed PMID: 25312468. 2: Powis RA, Mutsaers CA, Wishart TM, Hunter G, Wirth B, Gillingwater TH. Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target. Neuropathol Appl Neurobiol. 2014 Dec;40(7):873-87. doi: 10.1111/nan.12168. PubMed PMID: 25041530. 3: Xie M, Wang SH, Lu ZM, Pan Y, Chen QC, Liao XM. UCH-L1 inhibition involved in CREB dephosphorylation in hippocampal slices. J Mol Neurosci. 2014 May;53(1):59-68. doi: 10.1007/s12031-013-0197-z. Epub 2013 Dec 10. PubMed PMID: 24323362. 4: MartÃnez-Villarreal J, GarcÃa TardÃ³n N, IbÃ¡Ã±ez I, GimÃ©nez C, Zafra F. Cell surface turnover of the glutamate transporter GLT-1 is mediated by ubiquitination/deubiquitination. Glia. 2012 Sep;60(9):1356-65. doi: 10.1002/glia.22354. Epub 2012 May 16. PubMed PMID: 22593014. 5: Zhang M, Deng Y, Luo Y, Zhang S, Zou H, Cai F, Wada K, Song W. Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1. J Neurochem. 2012 Mar;120(6):1129-38. doi: 10.1111/j.1471-4159.2011.07644.x. Epub 2012 Feb 10. PubMed PMID: 22212137. 6: White RR, Miyata S, Papa E, Spooner E, Gounaris K, Selkirk ME, Artavanis-Tsakonas K. Characterisation of the Trichinella spiralis deubiquitinating enzyme, TsUCH37, an evolutionarily conserved proteasome interaction partner. PLoS Negl Trop Dis. 2011 Oct;5(10):e1340. doi: 10.1371/journal.pntd.0001340. Epub 2011 Oct 4. PubMed PMID: 22013496; PubMed Central PMCID: PMC3186758. 7: Hsu SH, Lai MC, Er TK, Yang SN, Hung CH, Tsai HH, Lin YC, Chang JG, Lo YC, Jong YJ. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) regulates the level of SMN expression through ubiquitination in primary spinal muscular atrophy fibroblasts. Clin Chim Acta. 2010 Dec 14;411(23-24):1920-8. doi: 10.1016/j.cca.2010.07.035. Epub 2010 Aug 14. PubMed PMID: 20713032. 8: Cartier AE, Djakovic SN, Salehi A, Wilson SM, Masliah E, Patrick GN. Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1. J Neurosci. 2009 Jun 17;29(24):7857-68. doi: 10.1523/JNEUROSCI.1817-09.2009. PubMed PMID: 19535597; PubMed Central PMCID: PMC2748938. 9: Tan YY, Zhou HY, Wang ZQ, Chen SD. Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor. Mol Cell Biochem. 2008 Nov;318(1-2):109-15. doi: 10.1007/s11010-008-9862-x. Epub 2008 Jul 12. PubMed PMID: 18622688. 10: Susor A, Ellederova Z, Jelinkova L, Halada P, Kavan D, Kubelka M, Kovarova H. Proteomic analysis of porcine oocytes during in vitro maturation reveals essential role for the ubiquitin C-terminal hydrolase-L1. Reproduction. 2007 Oct;134(4):559-68. PubMed PMID: 17890291.