Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors

Wünsch M, Senger J, Schultheisz P, Schwarzbich S, Schmidtkunz K, Michalek C, Klaß M, Goskowitz S, Borchert P, Praetorius L, Sippl W, et al. (2017)
ChemMedChem 12(24): 2044-2053.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
 
Download
Es wurden keine Dateien hochgeladen. Nur Publikationsnachweis!
Autor*in
Wünsch, MatthiasUniBi; Senger, Johanna; Schultheisz, Philipp; Schwarzbich, Sabrina; Schmidtkunz, Karin; Michalek, CarmelaUniBi; Klaß, MichaelaUniBi; Goskowitz, Stefanie; Borchert, Philipp; Praetorius, Lucas; Sippl, Wolfgang; Jung, Manfred
Alle
Abstract / Bemerkung
As histone deacetylases (HDACs) play an important role in the treatment of cancer, their selective inhibition has been the subject of various studies. These continuous investigations have given rise to a large collection of pan- and selective HDAC inhibitors, containing diverse US Food and Drug Administration (FDA)-approved representatives. In previous studies, a class of alkyne-based HDAC inhibitors was presented. We modified this scaffold in two previously neglected regions and compared their cytotoxicity and affinity toward HDAC1, HDAC6, and HDAC8. We were able to show that R-configured propargylamines contribute to increased selectivity for HDAC6. Docking studies on available HDAC crystal structures were carried out to rationalize the observed selectivity of the compounds. Substitution of the aromatic portion by a thiophene derivative results in high affinity and low cytotoxicity, indicating an improved drug tolerance.
Stichworte
cancer; heterocycles; histone deacetylase; inhibitors; propargylamine
Erscheinungsjahr
2017
Zeitschriftentitel
ChemMedChem
Band
12
Ausgabe
24
Seite(n)
2044-2053
ISSN
1860-7179
eISSN
1860-7187
Page URI
https://pub.uni-bielefeld.de/record/2917176

Zitieren

Wünsch M, Senger J, Schultheisz P, et al. Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors. ChemMedChem. 2017;12(24):2044-2053.
Wünsch, M., Senger, J., Schultheisz, P., Schwarzbich, S., Schmidtkunz, K., Michalek, C., Klaß, M., et al. (2017). Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors. ChemMedChem, 12(24), 2044-2053. doi:10.1002/cmdc.201700550
Wünsch, Matthias, Senger, Johanna, Schultheisz, Philipp, Schwarzbich, Sabrina, Schmidtkunz, Karin, Michalek, Carmela, Klaß, Michaela, et al. 2017. “Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors”. ChemMedChem 12 (24): 2044-2053.
Wünsch, M., Senger, J., Schultheisz, P., Schwarzbich, S., Schmidtkunz, K., Michalek, C., Klaß, M., Goskowitz, S., Borchert, P., Praetorius, L., et al. (2017). Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors. ChemMedChem 12, 2044-2053.
Wünsch, M., et al., 2017. Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors. ChemMedChem, 12(24), p 2044-2053.
M. Wünsch, et al., “Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors”, ChemMedChem, vol. 12, 2017, pp. 2044-2053.
Wünsch, M., Senger, J., Schultheisz, P., Schwarzbich, S., Schmidtkunz, K., Michalek, C., Klaß, M., Goskowitz, S., Borchert, P., Praetorius, L., Sippl, W., Jung, M., Sewald, N.: Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors. ChemMedChem. 12, 2044-2053 (2017).
Wünsch, Matthias, Senger, Johanna, Schultheisz, Philipp, Schwarzbich, Sabrina, Schmidtkunz, Karin, Michalek, Carmela, Klaß, Michaela, Goskowitz, Stefanie, Borchert, Philipp, Praetorius, Lucas, Sippl, Wolfgang, Jung, Manfred, and Sewald, Norbert. “Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors”. ChemMedChem 12.24 (2017): 2044-2053.

54 References

Daten bereitgestellt von Europe PubMed Central.

Histone deacetylase inhibitors: overview and perspectives.
Dokmanovic M, Clarke C, Marks PA., Mol. Cancer Res. 5(10), 2007
PMID: 17951399
Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation.
Cook C, Gendron TF, Scheffel K, Carlomagno Y, Dunmore J, DeTure M, Petrucelli L., Hum. Mol. Genet. 21(13), 2012
PMID: 22492994

Aldana-Masangkay, J. Biomed. Biotechnol. (), 2011
The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis.
Lee YS, Lim KH, Guo X, Kawaguchi Y, Gao Y, Barrientos T, Ordentlich P, Wang XF, Counter CM, Yao TP., Cancer Res. 68(18), 2008
PMID: 18794144
Histone deacetylase inhibitors in cancer therapy.
Lane AA, Chabner BA., J. Clin. Oncol. 27(32), 2009
PMID: 19826124
FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma.
Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R., Oncologist 12(10), 2007
PMID: 17962618
Trichostatin A-like hydroxamate histone deacetylase inhibitors as therapeutic agents: toxicological point of view.
Vanhaecke T, Papeleu P, Elaut G, Rogiers V., Curr. Med. Chem. 11(12), 2004
PMID: 15180568
Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101.
Plumb JA, Finn PW, Williams RJ, Bandara MJ, Romero MR, Watkins CJ, La Thangue NB, Brown R., Mol. Cancer Ther. 2(8), 2003
PMID: 12939461
R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies.
Arts J, Angibaud P, Marien A, Floren W, Janssens B, King P, van Dun J, Janssen L, Geerts T, Tuman RW, Johnson DL, Andries L, Jung M, Janicot M, van Emelen K., Br. J. Cancer 97(10), 2007
PMID: 18000499
Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase.
Kim YB, Lee KH, Sugita K, Yoshida M, Horinouchi S., Oncogene 18(15), 1999
PMID: 10229197
Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A.
Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP., J. Am. Chem. Soc. 132(31), 2010
PMID: 20614936
Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer.
Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist JP, Schwartz L, Richardson S, Chu E, Olgac S, Marks PA, Scher H, Richon VM., J. Clin. Oncol. 23(17), 2005
PMID: 15897550
Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity.
Ning ZQ, Li ZB, Newman MJ, Shan S, Wang XH, Pan DS, Zhang J, Dong M, Du X, Lu XP., Cancer Chemother. Pharmacol. 69(4), 2011
PMID: 22080169
Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression.
Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, Schuettengruber B, Hauser C, Brunmeir R, Jenuwein T, Seiser C., EMBO J. 21(11), 2002
PMID: 12032080
Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity.
Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, Floss T, Goettlicher M, Noppinger PR, Wurst W, Ferrari VA, Abrams CS, Gruber PJ, Epstein JA., Nat. Med. 13(3), 2007
PMID: 17322895
Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy.
Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN., Cell 110(4), 2002
PMID: 12202037
Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation.
Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL., Proc. Natl. Acad. Sci. U.S.A. 100(8), 2003
PMID: 12677000
Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally.
Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M, Cao C, Li N, Cheng HL, Chua K, Lombard D, Mizeracki A, Matthias G, Alt FW, Khochbin S, Matthias P., Mol. Cell. Biol. 28(5), 2008
PMID: 18180281
HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo.
Zhang Y, Li N, Caron C, Matthias G, Hess D, Khochbin S, Matthias P., EMBO J. 22(5), 2003
PMID: 12606581
Development and therapeutic impact of HDAC6-selective inhibitors.
Dallavalle S, Pisano C, Zunino F., Biochem. Pharmacol. 84(6), 2012
PMID: 22728920
Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation.
Dompierre JP, Godin JD, Charrin BC, Cordelieres FP, King SJ, Humbert S, Saudou F., J. Neurosci. 27(13), 2007
PMID: 17392473
Histone deacetylase inhibitors: possible implications for neurodegenerative disorders.
Hahnen E, Hauke J, Trankle C, Eyupoglu IY, Wirth B, Blumcke I., Expert Opin Investig Drugs 17(2), 2008
PMID: 18230051
Histone deacetylase 6 structure and molecular basis of catalysis and inhibition.
Hai Y, Christianson DW., Nat. Chem. Biol. 12(9), 2016
PMID: 27454933
Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors.
Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP., Nature 401(6749), 1999
PMID: 10490031
Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases.
Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, Luong C, Arvai A, Buggy JJ, Chi E, Tang J, Sang BC, Verner E, Wynands R, Leahy EM, Dougan DR, Snell G, Navre M, Knuth MW, Swanson RV, McRee DE, Tari LW., Structure 12(7), 2004
PMID: 15242608
Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity.
Schuetz A, Min J, Allali-Hassani A, Schapira M, Shuen M, Loppnau P, Mazitschek R, Kwiatkowski NP, Lewis TA, Maglathin RL, McLean TH, Bochkarev A, Plotnikov AN, Vedadi M, Arrowsmith CH., J. Biol. Chem. 283(17), 2008
PMID: 18285338
Structural biology: HDAC6 finally crystal clear.
Liu Y, Li L, Min J., Nat. Chem. Biol. 12(9), 2016
PMID: 27538024

AUTHOR UNKNOWN, 0
Click Chemistry: Diverse Chemical Function from a Few Good Reactions.
Kolb HC, Finn MG, Sharpless KB., Angew. Chem. Int. Ed. Engl. 40(11), 2001
PMID: 11433435

AUTHOR UNKNOWN, Angew. Chem. 113(), 2001
Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics.
Wunsch M, Schroder D, Frohr T, Teichmann L, Hedwig S, Janson N, Belu C, Simon J, Heidemeyer S, Holtkamp P, Rudlof J, Klemme L, Hinzmann A, Neumann B, Stammler HG, Sewald N., Beilstein J Org Chem 13(), 2017
PMID: 29234470

Cogan, Tetrahedron 55(), 1999
A fluorogenic histone deacetylase assay well suited for high-throughput activity screening.
Wegener D, Wirsching F, Riester D, Schwienhorst A., Chem. Biol. 10(1), 2003
PMID: 12573699
Improved fluorogenic histone deacetylase assay for high-throughput-screening applications.
Wegener D, Hildmann C, Riester D, Schwienhorst A., Anal. Biochem. 321(2), 2003
PMID: 14511685
In vitro assays for the determination of histone deacetylase activity.
Heltweg B, Trapp J, Jung M., Methods 36(4), 2005
PMID: 16087348
Approaches for the synthesis of functionalized cryptophycins.
Sammet B, Bogner T, Nahrwold M, Weiss C, Sewald N., J. Org. Chem. 75(20), 2010
PMID: 20857920
Insights into the activation mechanism of class I HDAC complexes by inositol phosphates.
Watson PJ, Millard CJ, Riley AM, Robertson NS, Wright LC, Godage HY, Cowley SM, Jamieson AG, Potter BV, Schwabe JW., Nat Commun 7(), 2016
PMID: 27109927
Structure of 'linkerless' hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket.
Tabackman AA, Frankson R, Marsan ES, Perry K, Cole KE., J. Struct. Biol. 195(3), 2016
PMID: 27374062
Nonisotopic substrate for assaying both human zinc and NAD+-dependent histone deacetylases.
Heltweg B, Dequiedt F, Verdin E, Jung M., Anal. Biochem. 319(1), 2003
PMID: 12842105
Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
Marek M, Kannan S, Hauser AT, Moraes Mourao M, Caby S, Cura V, Stolfa DA, Schmidtkunz K, Lancelot J, Andrade L, Renaud JP, Oliveira G, Sippl W, Jung M, Cavarelli J, Pierce RJ, Romier C., PLoS Pathog. 9(9), 2013
PMID: 24086136
The Protein Data Bank.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE., Nucleic Acids Res. 28(1), 2000
PMID: 10592235

AUTHOR UNKNOWN, 0

AUTHOR UNKNOWN, 0

AUTHOR UNKNOWN, 0
Three-Component Aminoalkylations Yielding Dihydronaphthoxazine-Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side-Chains.
Vojacek S, Beese K, Alhalabi Z, Swyter S, Bodtke A, Schulzke C, Jung M, Sippl W, Link A., Arch. Pharm. (Weinheim) 350(7), 2017
PMID: 28547816
Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis.
Heimburg T, Chakrabarti A, Lancelot J, Marek M, Melesina J, Hauser AT, Shaik TB, Duclaud S, Robaa D, Erdmann F, Schmidt M, Romier C, Pierce RJ, Jung M, Sippl W., J. Med. Chem. 59(6), 2016
PMID: 26937828
Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors.
Senger J, Melesina J, Marek M, Romier C, Oehme I, Witt O, Sippl W, Jung M., J. Med. Chem. 59(4), 2015
PMID: 26653328

AUTHOR UNKNOWN, 0
Export

Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®
Quellen

PMID: 29120081
PubMed | Europe PMC

Suchen in

Google Scholar