Selective Histone Deacetylase 6 Inhibitors Bearing Substituted Urea Linkers Inhibit Melanoma Cell Growth

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Sep 27

PMID 23009203

Citations 62

Authors

Joel A Bergman

Karrune Woan

Patricio Perez-Villarroel

Alejandro Villagra

Eduardo M Sotomayor

Alan P Kozikowski

Affiliations

Soon will be listed here.

Abstract

The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5 g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ∼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.

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References

Kelly W, Marks P . Drug insight: Histone deacetylase inhibitors--development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol. 2005; 2(3):150-7. DOI: 10.1038/ncponc0106. View

Guo D, Huang H, Xu J, Jiang H, Liu H . Efficient iron-catalyzed N-arylation of aryl halides with amines. Org Lett. 2008; 10(20):4513-6. DOI: 10.1021/ol801784a. View

Zou H, Wu Y, Navre M, Sang B . Characterization of the two catalytic domains in histone deacetylase 6. Biochem Biophys Res Commun. 2006; 341(1):45-50. DOI: 10.1016/j.bbrc.2005.12.144. View

Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F . Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor. J Med Chem. 2008; 51(14):4072-5. DOI: 10.1021/jm800251w. View

Gao L, Cueto M, Asselbergs F, Atadja P . Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J Biol Chem. 2002; 277(28):25748-55. DOI: 10.1074/jbc.M111871200. View

Peltonen K, Kiviharju T, Jarvinen P, Ra R, Laiho M . Melanoma cell lines are susceptible to histone deacetylase inhibitor TSA provoked cell cycle arrest and apoptosis. Pigment Cell Res. 2005; 18(3):196-202. DOI: 10.1111/j.1600-0749.2005.00225.x. View

Kalin J, Butler K, Akimova T, Hancock W, Kozikowski A . Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells. J Med Chem. 2011; 55(2):639-51. DOI: 10.1021/jm200773h. View

Wang H, Cheng F, Woan K, Sahakian E, Merino O, Rock-Klotz J . Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10. J Immunol. 2011; 186(7):3986-96. PMC: 3998678. DOI: 10.4049/jimmunol.1001101. View

Wagner J, Hackanson B, Lubbert M, Jung M . Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenetics. 2011; 1(3-4):117-136. PMC: 3020651. DOI: 10.1007/s13148-010-0012-4. View

10.

Santo L, Hideshima T, Kung A, Tseng J, Tamang D, Yang M . Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012; 119(11):2579-89. PMC: 3337713. DOI: 10.1182/blood-2011-10-387365. View

11.

Butler K, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski A . Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am Chem Soc. 2010; 132(31):10842-6. PMC: 2916045. DOI: 10.1021/ja102758v. View

12.

Parmigiani R, Xu W, Venta-Perez G, Erdjument-Bromage H, Yaneva M, Tempst P . HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Proc Natl Acad Sci U S A. 2008; 105(28):9633-8. PMC: 2443817. DOI: 10.1073/pnas.0803749105. View

13.

Facchetti F, Previdi S, Ballarini M, Minucci S, Perego P, La Porta C . Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors. Apoptosis. 2004; 9(5):573-82. DOI: 10.1023/B:APPT.0000038036.31271.50. View

14.

Okano K, Tokuyama H, Fukuyama T . Synthesis of secondary arylamines through copper-mediated intermolecular aryl amination. Org Lett. 2003; 5(26):4987-90. DOI: 10.1021/ol035942y. View

15.

Vickers C, Olsen C, Leman L, Ghadiri M . Discovery of HDAC Inhibitors That Lack an Active Site Zn(2+)-Binding Functional Group. ACS Med Chem Lett. 2014; 3(6):505-8. PMC: 4025844. DOI: 10.1021/ml300081u. View

16.

Villagra A, Cheng F, Wang H, Suarez I, Glozak M, Maurin M . The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol. 2008; 10(1):92-100. PMC: 3925685. DOI: 10.1038/ni.1673. View

17.

Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M . Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol. 2008; 28(5):1688-701. PMC: 2258784. DOI: 10.1128/MCB.01154-06. View

18.

Fournel M, Bonfils C, Hou Y, Yan P, Trachy-Bourget M, Kalita A . MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008; 7(4):759-68. DOI: 10.1158/1535-7163.MCT-07-2026. View

19.

Kwong F, Klapars A, Buchwald S . Copper-catalyzed coupling of alkylamines and aryl iodides: an efficient system even in an air atmosphere. Org Lett. 2002; 4(4):581-4. DOI: 10.1021/ol0171867. View