Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity.

There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3- b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.

[1]  F. Zanini,et al.  Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment , 2018, Antiviral research.

[2]  B. Lindenbach,et al.  Interactions between the Hepatitis C Virus Nonstructural 2 Protein and Host Adaptor Proteins 1 and 4 Orchestrate Virus Release , 2018, mBio.

[3]  S. Bavari,et al.  Discovering Drugs for the Treatment of Ebola Virus , 2017, Current Treatment Options in Infectious Diseases.

[4]  J. Dye,et al.  Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects , 2017, The Journal of clinical investigation.

[5]  F. Gosselin,et al.  Highly Regioselective and Practical Synthesis of 5-Bromo-4-chloro-3-nitro-7-azaindole , 2017 .

[6]  L. Van Meervelt,et al.  Carbonylation as a novel method for the assembly of pyrazine based oligoamide alpha-helix mimetics. , 2017, Organic & biomolecular chemistry.

[7]  Beeraiah Baire,et al.  Reactivity of indole-3-alkoxides in the absence of acids: Rapid synthesis of homo- bisindolylmethanes , 2016 .

[8]  Alan G. E. Wilson,et al.  Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[9]  Thomas Knauber,et al.  Palladium Catalyzed Monoselective α-Arylation of Sulfones and Sulfonamides with 2,2,6,6-Tetramethylpiperidine·ZnCl·LiCl Base and Aryl Bromides. , 2016, The Journal of organic chemistry.

[10]  C. Luo,et al.  Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors. , 2016, ACS medicinal chemistry letters.

[11]  S. Knapp,et al.  Family-wide Structural Analysis of Human Numb-Associated Protein Kinases , 2016, Structure.

[12]  Christoph Nitsche,et al.  The Medicinal Chemistry of Dengue Virus. , 2016, Journal of medicinal chemistry.

[13]  Elena Bekerman,et al.  Combating emerging viral threats , 2015, Science.

[14]  S. Genheden,et al.  The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities , 2015, Expert opinion on drug discovery.

[15]  J. Mulholland,et al.  AP-2-Associated Protein Kinase 1 and Cyclin G-Associated Kinase Regulate Hepatitis C Virus Entry and Are Potential Drug Targets , 2015, Journal of Virology.

[16]  Davidr . Evans,et al.  History of the Harvard ChemDraw project. , 2014, Angewandte Chemie.

[17]  E. Hennessy,et al.  Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity , 2014 .

[18]  P. Herdewijn,et al.  Discovery of dual death-associated protein related apoptosis inducing protein kinase 1 and 2 inhibitors by a scaffold hopping approach. , 2014, Journal of medicinal chemistry.

[19]  J. Delabar,et al.  Development of DANDYs, new 3,5-diaryl-7-azaindoles demonstrating potent DYRK1A kinase inhibitory activity. , 2013, Journal of medicinal chemistry.

[20]  P. Knochel,et al.  Full functionalization of the 7-azaindole scaffold by selective metalation and sulfoxide/magnesium exchange. , 2013, Angewandte Chemie.

[21]  A. Wilder-Smith,et al.  Epidemiology of dengue: past, present and future prospects , 2013, Clinical epidemiology.

[22]  Xuping Xie,et al.  Membrane Topology and Function of Dengue Virus NS2A Protein , 2013, Journal of Virology.

[23]  Chelsea M. Byrd,et al.  A Novel Inhibitor of Dengue Virus Replication That Targets the Capsid Protein , 2012, Antimicrobial Agents and Chemotherapy.

[24]  Y. Jacob,et al.  Identification and Targeting of an Interaction between a Tyrosine Motif within Hepatitis C Virus Core Protein and AP2M1 Essential for Viral Assembly , 2012, PLoS pathogens.

[25]  M. Marsh,et al.  The cell biology of receptor-mediated virus entry , 2011, The Journal of cell biology.

[26]  Jeremy R. Duvall,et al.  AAK1 identified as an inhibitor of neuregulin-1/ErbB4-dependent neurotrophic factor signaling using integrative chemical genomics and proteomics. , 2011, Chemistry & biology.

[27]  Randy J. Read,et al.  Overview of the CCP4 suite and current developments , 2011, Acta crystallographica. Section D, Biological crystallography.

[28]  Yuquan Wei,et al.  Design and synthesis of 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles and pyrazolo[3,4-b]pyridines for Aurora-A kinase inhibitors. , 2010, Bioorganic & Medicinal Chemistry Letters.

[29]  P. Emsley,et al.  Features and development of Coot , 2010, Acta crystallographica. Section D, Biological crystallography.

[30]  R. Kusurkar,et al.  A rapid method toward the synthesis of new substituted tetrahydro α-carbolines and α-carbolines , 2010 .

[31]  A. Fernández-Sesma,et al.  Dengue Virus Inhibits the Production of Type I Interferon in Primary Human Dendritic Cells , 2010, Journal of Virology.

[32]  Graeme Winter,et al.  xia2: an expert system for macromolecular crystallography data reduction , 2010 .

[33]  Randy J. Read,et al.  Acta Crystallographica Section D Biological , 2003 .

[34]  W. Kabsch.  XDS , 2010, Acta crystallographica. Section D, Biological crystallography.

[35]  C. Huang,et al.  The dengue virus type 2 envelope protein fusion peptide is essential for membrane fusion. , 2010, Virology.

[36]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[37]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[38]  Gavin Harper,et al.  Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. , 2008, Journal of medicinal chemistry.

[39]  R. Kuhn,et al.  Closing the door on flaviviruses: entry as a target for antiviral drug design. , 2008, Antiviral research.

[40]  Mukul R Jain,et al.  Synthesis and antidiabetic activity of 2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridines and thieno[2,3-b]pyridines. , 2007, Bioorganic & medicinal chemistry.

[41]  Randy J. Read,et al.  Phaser crystallographic software , 2007, Journal of applied crystallography.

[42]  L. Wodicka,et al.  A small molecule–kinase interaction map for clinical kinase inhibitors , 2005, Nature Biotechnology.

[43]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[44]  N. Sullivan,et al.  Ebola Virus Pathogenesis: Implications for Vaccines and Therapies , 2003, Journal of Virology.

[45]  G. Murshudov,et al.  Refinement of macromolecular structures by the maximum-likelihood method. , 1997, Acta crystallographica. Section D, Biological crystallography.

[46]  K. K. Halder,et al.  Pathogenesis of dengue haemorrhagic fever. , 1991, Journal of the Indian Medical Association.

[47]  Mindy I. Davis,et al.  A quantitative analysis of kinase inhibitor selectivity , 2008, Nature Biotechnology.