735
Views
47
CrossRef citations to date
0
Altmetric
Review

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature

, , , &
Pages 1183-1199 | Received 17 Jun 2017, Accepted 24 Jul 2017, Published online: 02 Aug 2017

References

  • Wu P, Nielsen TE, Clausen MH. Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discov Today. 2016;21:5–10.
  • Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015;36:422–439.
  • Wu P, Clausen MH, Nielsen TE. Allosteric small-molecule kinase inhibitors. Pharmacol Ther. 2015;156:59–68.
  • Müller S, Chaikuad A, Gray NS, et al. The ins and outs of selective kinase inhibitor development. Nat Chem Biol. 2015;11:818–821.
  • Aranda S, Laguna A, De La Luna S. DYRK family of protein kinases: evolutionary relationships, biochemical properties, and functional roles. Faseb J. 2011;25:449–462.
  • Becker W, Sippl W. Activation, regulation, and inhibition of DYRK1A. Febs J. 2011;278:246–256.
  • Kay LJ, Smulders-Srinivasan TK, Soundararajan M. Understanding the multifaceted role of human down syndrome kinase DYRK1A. Adv Protein Chem Struct Biol. 2016;105:127–171.
  • Himpel S, Panzer P, Eirmbter K, et al. Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A. Biochem J. 2001;359:497–505.
  • Soppa U, Schumacher J, Florencio Ortiz V, et al. The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and cyclin D1 and induces cell cycle exit and neuronal differentiation. Cell Cycle. 2014;13:2084–2100.
  • Kurabayashi N, Nguyen MD, Sanada K. DYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model. EMBO Rep. 2015;16:1548–1562.
  • Khor B, Gagnon JD, Goel G, et al. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. eLife. 2015;4:1–27.
  • Ori-McKenney KM, McKenney RJ, Huang HH, et al. Phosphorylation of β-tubulin by the Down syndrome kinase, minibrain/DYRK1A, regulates microtubule dynamics and dendrite morphogenesis. Neuron. 2016;90:551–563.
  • Tejedor FJ, Hämmerle B. MNB/DYRK1A as a multiple regulator of neuronal development. Febs J. 2011;278:223–235.
  • Grau C, Arató K, Fernández-Fernández JM, et al. DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors. Front Cell Neurosci. 2014;8:331.
  • Pozo N, Zahonero C, Fernández P, et al. Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth. J Clin Invest. 2013;123:2475–2487.
  • Luna J, Bofill-De Ros X, Di Vona C, et al. DYRK1A overexpression in pancreatic ductal adenocarcinoma contributes to tumor growth. Pancreatology. 2015;15:S19.
  • Wegiel J, Gong CX, Hwang YW. The role of DYRK1A in neurodegenerative diseases. Febs J. 2011;278:236–245.
  • Hämmerle B, Elizalde C, Galceran J, et al. The MNB/DYRK1A protein kinase: neurobiological functions and Down syndrome implications. J Neural Transm Suppl. 2003;67:129–137.
  • Altafaj X, Dierssen M, Baamonde C, et al. Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down’s syndrome. Hum Mol Genet. 2001;10:1915–1923.
  • Abbassi R, Johns TG, Kassiou M, et al. DYRK1A in neurodegeneration and cancer: molecular basis and clinical implications. Pharmacol Ther. 2015;151:87–98.
  • Becker W, Soppa U, Tejedor FJ. DYRK1A: a potential drug target for multiple Down syndrome neuropathologies. CNS Neurol Disord Drug Targets. 2014;13:26–33.
  • Duchon A, Herault Y. DYRK1A, a dosage-sensitive gene involved in neurodevelopmental disorders, is a target for drug development in Down syndrome. Front Behav Neurosci. 2016;10:104.
  • Shen W, Taylor B, Jin Q, et al. Inhibition of DYRK1A and GSK3β induces human β-cell proliferation. Nat Commun. 2015;6:8372.
  • Belgardt BF, Lammert E. DYRK1A: A promising drug target for islet transplant-based diabetes therapies. Diabetes. 2016;65:1496–1498.
  • Dirice E, Walpita D, Vetere A, et al. Inhibition of DYRK1A stimulates human β-cell proliferation. Diabetes. 2016;65:1660–1671.
  • Radhakrishnan A, Nanjappa V, Raja R, et al. A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma. Sci Rep. 2016;6:36132.
  • Khor B. Regulatory T cells: central concepts from ontogeny to therapy. Transfus Med Rev. 2017;31:36–44.
  • Bendjeddou LZ, Loaëc N, Villiers B, et al. Exploration of the imidazo[1,2-b]pyridazine scaffold as a protein kinase inhibitor. Eur J Med Chem. 2017;125:696–709.
  • Meijer L, unpublished data
  • Smith B, Medda F, Gokhale V, et al. Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: a new avenue for a disease modifying treatment of Alzheimer’s? ACS Chem Neurosci. 2012;3:857–872.
  • Stotani S, Giordanetto F, Medda F. DYRK1A inhibition as potential treatment for Alzheimer’s disease. Future Med Chem. 2016;8:681–696.
  • Bain J, Plater L, Elliott M, et al. The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007;408:297–315.
  • Grabher P, Durieu E, Kouloura I, et al. Library-based discovery of DYRK1A/CLK1 inhibitors from natural product extracts. Planta Medica. 2012;78:951–956.
  • Bain J, McLauchlan H, Elliott M, et al. The specificities of protein kinase inhibitors: an update. Biochem J. 2003;371:199–204.
  • Debdab M, Carreaux F, Renault S, et al. Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J Med Chem. 2011;54:4172–4186.
  • Tahtouh T, Elkins JM, Filippakopoulos P, et al. Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B. J Med Chem. 2012;55:9312–9330.
  • Muraki M, Ohkawara B, Hosoya T, et al. Manipulation of alternative splicing by a newly developed inhibitor of Clks. J Biol Chem. 2004;279:24246–24254.
  • Chaikuad A, Diharce J, Schröder M, et al. An unusual binding model of the methyl 9-anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) confers high selectivity for dual-specificity tyrosine phosphorylation-regulated kinases. J Med Chem. 2016;59:10315–10321.
  • CNRS (FR) and University of Orléans (FR). Pyrido[3,2-d]pyrimidine derivatives, processes for preparing same and therapeutic uses thereof. WO135259; 2011
  • Dehbi O, Guillaumet G, Routier S, et al. Synthesis and optimization of an original V-shaped collection of 4-7-disubstituted Pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors. Eur J Med Chem. 2014;80:352–363.
  • Kassis P, Routier S, Guillaumet G, et al. Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5-(phenyl) pyridine or pyrazine V-shaped molecules as kinase inhibitors an cytotoxic agents. Eur J Med Chem. 2011;46:5416–5434.
  • F Hoffman-La Roche, AG. Pyrido pyrimidines for use as DYRK1 inhibitors. WO098065; 2012
  • Hoffman-La Roche F, AG (US). Pyrido pyrimidines. US0184542; 2012
  • Anderson K, Chen Y, Luk KC, et al. Pyrido[2,3-d]pyrimidines: discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors. Bioorg Med Chem Lett. 2013;23:6610–6615.
  • Perandones F, Soto JL. Synthesis of .pyrido[2,3-d]pyrimidines from aminopyrimidine carbaldehydes. J Het Chem. 1998;35:413–419.
  • F Hoffman-La Roche, AG (US). 1,6- and 1,8-naphthyridines useful as Dyrk1 inhibitors. WO098066; 2012
  • F Hoffman-La Roche, AG. Pyrazolopyrimidines as DYRK1A and DYRK1B inhibitors. WO098068; 2012
  • Bioduro (Beijing) Company Ltd. (CN), F Hoffmann-La Roche AG (CH), Hoffmann-La Roche Inc. (US). Preparation of pyrazolopyrimidines as inhibitors of DYRK1A and DYRK1B. US0184508; 2012
  • Laboratoires Servier (FR) and Vernalis (UK). New pyrrolo[2,3-d]pyrimidine derivatives as dual DYRK1A/CLK1 inhibitors. WO055533; 2017
  • Hoffman-La Roche F, Quinoline AG DYRK1 inhibitors. WO098070; 2012
  • Department of Health and Human Services (NIH, Bethesda, US). Quinazolin-4-amine derivatives; and methods of use. WO0041655; 2011
  • Mott BT, Tanega C, Shen M, et al. Evaluation of substituted 6-arylquinazolin-4-amines as potent and selective inhibitors of cdc2-like kinases (Clk). Bioorg Med Chem Lett. 2009;19:6700–6705.
  • Rosenthal AS, Tanega C, Shen M, et al. Potent and selective small molecule inhibitors of specific isoforms of Cdc2-like kinases (Clk) and dual specificity tyrosine-phosphorylation-regulated kinases (DYRK). Bioorg Med Chem Lett. 2011;21:3152–3158.
  • Exonhit SA (FR/US). DYRK1 inhibitors and uses thereof. WO 026806 A1; 2013
  • Foucourt A, Hedou D, Dubouilh-Benard C, et al. Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part I. Molecules. 2014;19:15546–15571.
  • Foucourt A, Hedou D, Dubouilh-Benard C, et al. Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II. Molecules. 2014;19:15411–15439.
  • Gunosewoyo H, Yu L, Munoz L, et al. Kinase targets in CNS drug discovery. Future Med Chem. 2017;7:303–314.
  • Hedou D, Godeau J, Loaec N, et al. Synthesis of thiazolo[5,4-f]quinazolin-9(8H)-ones as multi-target directed ligands of Ser/Thr kinases. Molecules. 2016;21:578.
  • Hedou D, Dubouilh-Benard C, Loaec N, et al. Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff reaction or Cu- catalyzed intramolecular C-S bond formation. Molecules. 2016;21:794.
  • Debray J, Bonte S, Lozach O, et al. catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors. Mol Divers. 2012;16:659–667.
  • CNRS (FR), University of Reims Champagne-Ardennes (FR), University of Paris 7 (FR). 3,5-Diarylazaindoles as DYRK1A protein inhibitors for the treatment of cognitive deficiencies associated with Down’s syndrome and with Alzheimer’s disease. WO096093; 2014
  • Gourdain S, Dairou J, Denhez C, et al. Development of DANDYs new 3.5-diaryl-7-azaindoles demonstrating potent DYRK1A kinase inhibitory activity. J Med Chem. 2013;56:9569–9585.
  • Merour JY, Routier S, Suzenet F, et al.; For synthetic strategies see. Recent advances in the synthesis and properties of 4-, 5-, 6-, or 7-azaindoles. Tetrahedron. 2013;69:4767–4834.
  • Echalier A, Bettayed K, Ferandin Y, et al. Meriolins (3-pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects and structure of a CDK2/cyclin A/Meriolin complex. J Med Chem. 2008;51:737–751.
  • CNRS (FR). Pyrrolo[2,3-b]pyridine compounds, azaindole compounds used for synthesizing said pyrrolo[2,3-b]pyridine compounds, methods for the production thereof, and uses thereof. WO2008/129152; 2008
  • Giraud F, Alves G, Debiton E, et al. Synthesis, protein kinase inhibitory potencies, and in vitro antiproliferative activities of Meriolin derivatives. J Med Chem. 54:4474–4489.
  • Zhou Q, Phoa EF, Abbassi RH, et al. Structure optimization and pharmacological evaluation of inhibitors targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and CDC-like kinases (CLK) in gioblastoma. J Med Chem. 2017;60:2052–2070.
  • Samumed, LLC (US). 5-Substituted indazole-3-carboxamides and preparation and use thereof. WO143380; 2015
  • Sirtris Pharmaceuticals, Inc. (US). Inhibitors of CDC2-like Kinases (CLKS) and methods of use thereof. WO085226;2009.
  • Kinopharma, Inc. (JP). Pharmaceutical composition comprising DYRK-inhibiting compound. W0010797; 2010
  • Ogawa Y, Nonaka Y, Goto T, et al. Development of a novel selective inhibitor of the Down syndrome-related kinase DYRK1A. Nat Commun. 2010;86:1–9.
  • Gupta AK, Ben-Mahmud A, Kamphuis LJ, et al. Methine bases in the benzothiazole, benzoselenazole, and quinolone series, and geometry and conformational preferences of their acyl derivatives. Can J Chem. 1995;73:1278–1286.
  • Univ Kyoto (Japan). soCompound pertaining to neuropoiesis and drug composition. WO083750; 2015
  • Masaki S, Kii I, Sumida Y, et al. Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a suppressor of adipogenesis. Bioorg Med Chem. 2015;23:4434–4441.
  • Lytix Biopharma As (Norway). Neurodegenerative therapies. WO118026; 2015
  • Rothweiler U, Eriksson J, Stensen W, et al. Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors. Eur J Med Chem. 2015;94:140–148.
  • Rothweiler U, Stensen W, Brandsdal BO, et al. Probing the ATP-binding pocket of protein kinase DYRK1A with benzothiazole fragment molecules. J Med Chem. 2016;59:9814–9824.
  • Selvita, SP. (PL). A compound, a process for its preparation, a pharmaceutical composition, use of compound, a method for modulating, or regulating serine/threonine kinases and a serine/threonine kinases modulating agent. WO058139; 2011
  • Selvita SA (PL). Novel benzimidazole derivatives as kinase inhibitors. WO096388; 2014
  • Pagano MA, Bain J, Kazimierczuk Z, et al. The selectivity of inhibitors of protein kinase CK2: an update. Biochem J. 2008;415:353–365.
  • Pagano MA, Andrzejewska M, Ruzzene M, et al. Optimization of protein kinase CK2 inhibitors derived form 4,5,6,7-tetrabromobenzimidazoles. J Med Chem. 2004;47:6239–6247.
  • The Arizona Board of Regents on behalf of the University of Arizona (US). Small molecule inhibitors of DYRK1A and uses thereof. WO040993; 2017
  • Laboratoires Servier (FR) and Vernalis (UK). New imidazo[4,5-b]pyridine derivatives as dual DYRK1A/CLK1 inhibitors. WO055530; 2017
  • The Brigham and women’s hospital, Inc. (US). Beta-carbolines as inhibitors of haspin and DYRK kinases. WO133795; 2011
  • Cuny GD, Ulyanova NP, Patnaik D, et al. Structure-activity retationship study of beta-carboline derivatives as haspin kinase inhibitors. Bioorg Med Chem. 2012;22:2015–2019.
  • The Brigham and women’s hospital, Inc. (US). Acridines as inhibitors of haspin and DYRK kinases. WO127406; 2011
  • Translational Genomics Research Institute (US). Compounds that inhibit Tau phosphorylation. WO024433; 2012
  • Medipropharma, Inc. (US). Compositions and methods for inhibiting DYRK1A to treat central nervous system diseases and disorders. WO068990; 2011
  • Frost D, Meechoovet B, Wang T, et al. β-Carboline compounds, including harmine, inhibit DYRK1A and Tau phosphorylation at multiple Alzheimer’s disease-related sites. PlosOne. 2011;6:e19264.
  • CNRS (FR). Kinases inhibitors. WO115071; 2014
  • Labriere C, Lozach O, Blairvacq M, et al. Further investigation of Paprotrain: towards the conception of selective and multi-targeted CNS kinase inhibitors. Eur J Med Chem. 2016;124:920–934.
  • Vahter J, Viht K, Uri A, et al. Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar inhibitors of CK2. Bioorg Med Chem Lett. 2017;25:2277–2284.
  • Pierre F, Chua PC, O’Brien SE, et al. Discovey and SAR of 5-[(3-chlorophenyl)amino] benzo[c][2,6]naphthyridine-8-carboxylic (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer. J Med Chem. 2011;54:635–654.
  • Korea Research Institute of Bioscience and Technology (KR). Pharmaceutical composition for preventing and treating degenerative brain diseases, containing CX-4945 as active ingredient. WO199503; 2015
  • Kim H, Lee K-S, Kim A-K, et al. A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition. Dis Model Mech. 2016;9:839–848.
  • Université de Rennes I and CNRS (FR). Imidazolone derivatives, preparation method thereof and biological use of same. WO050352; 2009
  • Fant X, Durieu E, Chicanne G, et al. Cdc-like/dual-specificity tyrosine phosphorylation-regulated kinases Leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer’s disease. Mol Pharmacol. 2014;85:441–450.
  • De la Torre R, De Sola S, Pons M, et al. Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol Nutr Food Res. 2014;58:278–288.
  • De la Torre R, De Sola S, Hernandez G, et al. TESDAD study group. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down’s syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:801–810.
  • Cascella M, Bimonte S, Muzio MR, et al. The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: an overview of pre-clinical studies and translational perspectives in clinical practice. Infect Agent Cancer. 2017;19:12–36.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.