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Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core.

Sivaprakasam P, Han X, Civiello RL, Jacutin-Porte S, Kish K, Pokross M, Lewis HA, Ahmed N, Szapiel N, Newitt JA, Baldwin ET, Xiao H, Krause CM, Park H, Nophsker M, Lippy JS, Burton CR, Langley DR, Macor JE, Dubowchik GM
Bioorg Med Chem Lett 25 1856-63 (2015)
Related entries: 4ptc, 4ptg

Cited: 26 times
EuropePMC logo PMID: 25845281

Abstract

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.

Articles - 4pte mentioned but not cited (3)

  1. A facile consensus ranking approach enhances virtual screening robustness and identifies a cell-active DYRK1α inhibitor. Mavrogeni ME, Pronios F, Zareifi D, Vasilakaki S, Lozach O, Alexopoulos L, Meijer L, Myrianthopoulos V, Mikros E. Future Med Chem 10 2411-2430 (2018)
  2. ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders. Demuro S, Sauvey C, Tripathi SK, Di Martino RMC, Shi D, Ortega JA, Russo D, Balboni B, Giabbai B, Storici P, Girotto S, Abagyan R, Cavalli A. Eur J Med Chem 229 114054 (2022)
  3. Naphthoquinone as a New Chemical Scaffold for Leishmanicidal Inhibitors of Leishmania GSK-3. Sebastián-Pérez V, Martínez de Iturrate P, Nácher-Vázquez M, Nóvoa L, Pérez C, Campillo NE, Gil C, Rivas L. Biomedicines 10 1136 (2022)


Reviews citing this publication (6)

  1. Multitarget Therapeutic Strategies for Alzheimer's Disease: Review on Emerging Target Combinations. Maramai S, Benchekroun M, Gabr MT, Yahiaoui S. Biomed Res Int 2020 5120230 (2020)
  2. Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer's Disease Therapy. Zagórska A, Jaromin A. Molecules 25 E3337 (2020)
  3. Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease. Benn CL, Dawson LA. Front Aging Neurosci 12 242 (2020)
  4. Current Pharmacotherapy and Multi-Target Approaches for Alzheimer's Disease. Cheong SL, Tiew JK, Fong YH, Leong HW, Chan YM, Chan ZL, Kong EWJ. Pharmaceuticals (Basel) 15 1560 (2022)
  5. Computer Aided Drug Design Methodologies with Natural Products in the Drug Research Against Alzheimer's Disease. de Sousa NF, Scotti L, de Moura ÉP, Dos Santos Maia M, Rodrigues GCS, de Medeiros HIR, Lopes SM, Scotti MT. Curr Neuropharmacol 20 857-885 (2022)
  6. Role of GSK-3β Inhibitors: New Promises and Opportunities for Alzheimer's Disease. Shri SR, Manandhar S, Nayak Y, Pai KSR. Adv Pharm Bull 13 688-700 (2023)

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  1. Identifying natural compounds as multi-target-directed ligands against Alzheimer's disease: an in silico approach. Ambure P, Ambure P, Bhat J, Puzyn T, Roy K. J Biomol Struct Dyn 37 1282-1306 (2019)
  2. Glycogen Synthase Kinase 3β: A New Gold Rush in Anti-Alzheimer's Disease Multitarget Drug Discovery? De Simone A, Tumiatti V, Andrisano V, Milelli A. J Med Chem 64 26-41 (2021)
  3. Dual GSK-3β/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer's Disease Drug Discovery. Jiang XY, Jiang XY, Chen TK, Zhou JT, He SY, Yang HY, Chen Y, Qu W, Feng F, Sun HP. ACS Med Chem Lett 9 171-176 (2018)
  4. 3D-e-Chem: Structural Cheminformatics Workflows for Computer-Aided Drug Discovery. Kooistra AJ, Vass M, McGuire R, Leurs R, de Esch IJP, Vriend G, Verhoeven S, de Graaf C. ChemMedChem 13 614-626 (2018)
  5. Multitarget Approach to Drug Candidates against Alzheimer's Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets. Ivanova L, Karelson M, Dobchev DA. Molecules 25 E1846 (2020)
  6. In silico screening and identification of potential GSK3β inhibitors. Daggupati T, Pamanji R, Yeguvapalli S. J Recept Signal Transduct Res 38 279-289 (2018)
  7. Integrating Machine Learning-Based Virtual Screening With Multiple Protein Structures and Bio-Assay Evaluation for Discovery of Novel GSK3β Inhibitors. Zhu J, Wu Y, Wang M, Li K, Xu L, Chen Y, Cai Y, Jin J. Front Pharmacol 11 566058 (2020)
  8. How to design potent and selective DYRK1B inhibitors? Molecular modeling study. Szamborska-Gbur A, Rutkowska E, Dreas A, Frid M, Vilenchik M, Milik M, Brzózka K, Król M. J Mol Model 25 41 (2019)
  9. Identification of dual kinase inhibitors of CK2 and GSK3β: combined qualitative and quantitative pharmacophore modeling approach. Pardhi T, Vasu K. J Biomol Struct Dyn 36 177-194 (2018)
  10. Uniting Amide Synthesis and Activation by PIII/PV-Catalyzed Serial Condensation: Three-Component Assembly of 2-Amidopyridines. Lipshultz JM, Radosevich AT. J Am Chem Soc 143 14487-14494 (2021)
  11. Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors. Andreev S, Pantsar T, Ansideri F, Kudolo M, Forster M, Schollmeyer D, Laufer SA, Koch P. Molecules 24 E2331 (2019)
  12. A protein interaction free energy model based on amino acid residue contributions: Assessment of point mutation stability of T4 lysozyme. Williams LJ, Schendt BJ, Fritz ZR, Attali Y, Lavroff RH, Yarmush ML. Technology (Singap World Sci) 7 12-39 (2019)
  13. Discovery and Evaluation of Enantiopure 9H-pyrimido[4,5-b]indoles as Nanomolar GSK-3β Inhibitors with Improved Metabolic Stability. Andreev S, Pantsar T, El-Gokha A, Ansideri F, Kudolo M, Anton DB, Sita G, Romasco J, Geibel C, Lämmerhofer M, Goettert MI, Tarozzi A, Laufer SA, Koch P. Int J Mol Sci 21 E7823 (2020)
  14. Pyridinylimidazoles as GSK3β Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks. Heider F, Pantsar T, Kudolo M, Ansideri F, De Simone A, Pruccoli L, Schneider T, Goettert MI, Tarozzi A, Andrisano V, Laufer SA, Koch P. ACS Med Chem Lett 10 1407-1414 (2019)
  15. 2-Amino Thiazole Derivatives as Prospective Aurora Kinase Inhibitors against Breast Cancer: QSAR, ADMET Prediction, Molecular Docking, and Molecular Dynamic Simulation Studies. Bathula S, Sankaranarayanan M, Malgija B, Kaliappan I, Bhandare RR, Shaik AB. ACS Omega 8 44287-44311 (2023)
  16. Identification and validation of G protein-coupled receptors modulating flow-dependent signaling pathways in vascular endothelial cells. Qiu D, Xu K, Chung N, Robbins J, Luo R, Lawrence M, He A, Yu F, Alt A, Miller MM, Hangeland J, Feder JN, Seiffert D, Arey BJ. Front Mol Biosci 10 1198079 (2023)
  17. Synthesis and biological evaluation of thieno[3,2-c]pyrazol-3-amine derivatives as potent glycogen synthase kinase 3β inhibitors for Alzheimer's disease. Yan N, Shi XL, Tang LQ, Wang DF, Li X, Liu C, Liu ZP. J Enzyme Inhib Med Chem 37 1724-1736 (2022)


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