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3 - Alzheimer’s Disease Drug Discovery in Academia: From High-Throughput Screening to In Vivo Testing

from Section 1 - Advancing Alzheimer’s Disease Therapies in a Collaborative Science Ecosystem

Published online by Cambridge University Press:  03 March 2022

Jeffrey Cummings
Affiliation:
University of Nevada, Las Vegas
Jefferson Kinney
Affiliation:
University of Nevada, Las Vegas
Howard Fillit
Affiliation:
Alzheimer’s Drug Discovery Foundation
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Summary

There is a tremendous need for disease-modifying treatments for Alzheimer’s disease (AD). The pharmaceutical sector has expended considerable resources on AD drug discovery, yet to date have obtained regulatory approval for only one agent that slows AD progression. This has led to increased interest in identifying new AD drug targets and disease mechanisms. Academic laboratories can play a meaningful role in the validation of AD drug targets and the identification of molecular probes that modulate these targets. We discuss here how academic researchers can contribute to the AD drug discovery process. This includes examples of assays that have been used for AD small molecule screens within academic laboratories, and discussions on assay optimization for compound screening, the selection of molecular libraries, and the iterative process of compound optimization to identify molecules suitable for advancement to in vivo pharmacokinetic, safety, and efficacy testing. Finally, we outline how academic researchers might work with pharmaceutical partners in AD drug discovery, and note the pros and cons of such collaborations.

Type
Chapter
Information
Alzheimer's Disease Drug Development
Research and Development Ecosystem
, pp. 34 - 44
Publisher: Cambridge University Press
Print publication year: 2022

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References

Cacace, R, Sleegers, K, Van Broeckhoven, C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement 2016; 12: 733–48.CrossRefGoogle ScholarPubMed
Joe, E, Ringman, JM. Cognitive symptoms of Alzheimer’s disease: clinical management and prevention. BMJ 2019; 367: l6217.Google Scholar
Cummings, J, Lee, G, Ritter, A, Sabbagh, M, Zhong, K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement (N Y) 2019; 5: 272–93.Google Scholar
Hardy, J. The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the “amyloid cascade hypothesis”. FEBS J 2017; 284: 1040–4.Google Scholar
George-Hyslop, PH, Petit, A. Molecular biology and genetics of Alzheimer’s disease. CR Biol 2005; 328: 119–30.Google Scholar
Jack, CR, Jr., Knopman, DS, Jagust, WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013; 12: 207–16.CrossRefGoogle ScholarPubMed
McDade, E, Wang, G, Gordon, BA, et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 2018; 91: e1295–306.Google Scholar
Khanna, MR, Kovalevich, J, Lee, VM, Trojanowski, JQ, Brunden, KR. Therapeutic strategies for the treatment of tauopathies: hopes and challenges. Alzheimers Dement 2016; 12: 1051–65.Google Scholar
Arriagada, PV, Growdon, JH, Hedleywhyte, ET, Hyman, BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimers disease. Neurology 1992; 42: 631–9.CrossRefGoogle ScholarPubMed
Teng, E, Ward, M, Manser, PT, et al. Cross-sectional associations between [(18)F]GTP1 tau PET and cognition in Alzheimer’s disease. Neurobiol Aging 2019; 81: 138–45.Google Scholar
Malik, M, Parikh, I, Vasquez, JB, et al. Genetics ignite focus on microglial inflammation in Alzheimer’s disease. Mol Neurodegener 2015; 10: 52.Google Scholar
Taniguchi, S, Suzuki, N, Masuda, M, et al. Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem 2005; 280: 7614–23.CrossRefGoogle ScholarPubMed
Honson, NS, Johnson, RL, Huang, WW, et al. Differentiating Alzheimer disease-associated aggregates with small molecules. Neurobiol Dis 2007; 28: 251–60.Google Scholar
Crowe, A, Ballatore, C, Hyde, E, Trojanowski, JQ, Lee, VMY. High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation. Biochem Biophys Res Commun 2007; 358: 16.Google Scholar
Crowe, A, Huang, W, Ballatore, C, et al. The identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry 2009; 48: 7732–45.Google Scholar
Pickhardt, M, Gazova, Z, von Bergen, M, et al. Anthraquinones inhibit tau aggregation and dissolve Alzheimer’s paired helical filaments in vitro and in cells. J Biol Chem 2005; 280: 3628–35.CrossRefGoogle ScholarPubMed
Crowe, A, James, MJ, Lee, VM, et al. Aminothienopyridazines and methylene blue affect tau fibrillization via cysteine oxidation. J Biol Chem 2013; 288: 11024–37.Google Scholar
Pickhardt, M, Tassoni, M, Denner, P, et al. Screening of a neuronal cell model of tau pathology for therapeutic compounds. Neurobiol Aging 2019; 76: 2434.Google Scholar
Khlistunova, I, Biernat, J, Wang, YP, et al. Inducible expression of tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 2006; 281: 1205–14.Google Scholar
Crowe, A, Henderson, MJ, Anderson, J, et al. Compound screening in cell-based models of tau inclusion formation: comparison of primary neuron and HEK293 cell assays. J Biol Chem 2020; 295: 4001–13.Google Scholar
Guo, JL, Narasimhan, S, Changolkar, L, et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med 2016; 213: 2635–54.Google Scholar
McCormick, AV, Wheeler, JM, Guthrie, CR, Liachko, NF, Kraemer, BC. Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity. Biol Psychiatry 2013; 73: 464–71.Google Scholar
Kow, RL, Sikkema, C, Wheeler, JM, et al. DOPA decarboxylase modulates tau toxicity. Biol Psychiatry 2018; 83: 438–46.Google Scholar
Ballatore, C, Lee, VMY, Trojanowski, JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 2007; 8: 663–72.Google Scholar
Tell, V, Hilgeroth, A. Recent developments of protein kinase inhibitors as potential AD therapeutics. Front Cell Neurosci 2013; 7:189.CrossRefGoogle ScholarPubMed
Martin, L, Latypova, X, Wilson, CM, et al. Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev 2013; 12: 289309.Google Scholar
Zeb, A, Son, M, Yoon, S, et al. Computational simulations identified two candidate inhibitors of CDK5/p25 to abrogate tau-associated neurological disorders. Comput Struct Biotechnol J 2019; 17: 579–90.Google Scholar
Shukla, R, Munjal, NS, Singh, TR. Identification of novel small molecules against GSK3beta for Alzheimer’s disease using chemoinformatics approach. J Mol Graph Model 2019; 91: 91104.CrossRefGoogle ScholarPubMed
Lin, CH, Hsieh, YS, Wu, YR, et al. Identifying GSK-3beta kinase inhibitors of Alzheimer’s disease: virtual screening, enzyme, and cell assays. Eur J Pharm Sci 2016; 89: 11–19.CrossRefGoogle ScholarPubMed
Bhat, RV, Andersson, U, Andersson, S, et al. The conundrum of GSK3 inhibitors: is it the dawn of a new beginning? J Alzheimers Dis 2018; 64: S547–54.CrossRefGoogle ScholarPubMed
Dehdashti, SJ, Zheng, W, Gever, JR, et al. A high-throughput screening assay for determining cellular levels of total tau protein. Curr Alzheimer Res 2013; 10: 679–87.CrossRefGoogle ScholarPubMed
Wang, C, Ward, ME, Chen, R, et al. Scalable production of iPSC-derived human neurons to identify tau-lowering compounds by high-content screening. Stem Cell Reports 2017; 9: 1221–33.CrossRefGoogle ScholarPubMed
Silva, MC, Nandi, GA, Tentarelli, S, et al. Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons. Nat Commun 2020; 11: 3258.Google Scholar
Coussens, NP, Sittampalam, GS, Guha, R, et al. Assay Guidance Manual: quantitative biology and pharmacology in preclinical drug discovery. Clin Transl Sci 2018; 11: 461–70.CrossRefGoogle ScholarPubMed
Zhang, JH, Chung, TDY, Oldenburg, KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 1999; 4: 6773.Google Scholar
Dandapani, S, Rosse, G, Southall, N, Salvino, JM, Thomas, CJ. Selecting, acquiring, and using small molecule libraries for high-throughput screening. Curr Protocol Chem Biol 2012; 4: 177–91.Google Scholar
Caldwell, GW. In silico tools used for compound selection during target-based drug discovery and development. Expert Opin Drug Discov 2015; 10: 901–23.CrossRefGoogle ScholarPubMed
Pardridge, WM. The blood–brain barrier: bottleneck in brain drug development. NeuroRx 2005; 2: 314.CrossRefGoogle ScholarPubMed
Hitchcock, SA. Blood–brain barrier permeability considerations for CNS-targeted compound library design. Curr Opin Chem Biol 2008; 12: 318–23.Google Scholar
Lipinski, CA, Lombardo, F, Dominy, BW, Feeney, PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliver Rev 1997; 23: 325.Google Scholar
Dahlin, JL, Nissink, JW, Strasser, JM, et al. PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS. J Med Chem 2015; 58: 2091–113.Google Scholar
Bruns, RF, Watson, IA. Rules for identifying potentially reactive or promiscuous compounds. J Med Chem 2012; 55: 9763–72.CrossRefGoogle ScholarPubMed
Wager, TT, Hou, X, Verhoest, PR, Villalobos, A. Central nervous system multiparameter optimization desirability: application in drug discovery. ACS Chem Neurosci 2016; 7: 767–75.Google Scholar
Hopkins, AL, Keseru, GM, Leeson, PD, Rees, DC, Reynolds, CH. The role of ligand efficiency metrics in drug discovery. Nat Rev Drug Discov 2014; 13: 105–21.CrossRefGoogle ScholarPubMed
Meanwell, NA. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem Res Toxicol 2016; 29: 564616.Google Scholar
Dimitriadi, M, Hart, AC. Neurodegenerative disorders: insights from the nematode Caenorhabditis elegans. Neurobiol Dis 2010; 40: 411.Google Scholar
McGurk, L, Berson, A, Bonini, NM. Drosophila as an in vivo model for human neurodegenerative disease. Genetics 2015; 201: 377402.Google Scholar
Bicker, J, Alves, G, Fortuna, A, Falcao, A. Blood–brain barrier models and their relevance for a successful development of CNS drug delivery systems: a review. Eur J Pharm Biopharm 2014; 87: 409–32.Google Scholar
Kovalevich, J, Cornec, AS, Yao, Y, et al. Characterization of brain-penetrant pyrimidine-containing molecules with differential microtubule-stabilizing activities developed as potential therapeutic agents for Alzheimer’s disease and related tauopathies. J Pharmacol Exp Ther 2016; 357: 432–50.Google Scholar
Di, L, Umland, JP, Chang, G, et al. Species independence in brain tissue binding using brain homogenates. Drug Metab Dispos 2011; 39: 1270–7.Google Scholar
Di, L, Rong, H, Feng, B. Demystifying brain penetration in central nervous system drug discovery. Miniperspective. J Med Chem 2013; 56: 212.Google Scholar
Benet, LZ, Zia-Amirhosseini, P. Basic principles of pharmacokinetics. Toxicol Pathol 1995; 23: 115–23.Google Scholar
Gaskill, BN, Garner, JP. Power to the people: power, negative results and sample size. J Am Assoc Lab Anim Sci 2020; 59: 916.CrossRefGoogle Scholar
Snyder, HM, Shineman, DW, Friedman, LG, et al. Guidelines to improve animal study design and reproducibility for Alzheimer’s disease and related dementias: for funders and researchers. Alzheimers Dement 2016; 12: 1177–85.CrossRefGoogle ScholarPubMed
Guo, JL, Buist, A, Soares, A, et al. The dynamics and turnover of tau aggregates in cultured cells: insights into therapies for tauopathies. J Biol Chem 2016; 291: 13175–93.CrossRefGoogle ScholarPubMed
Sankaranarayanan, S, Barten, DM, Vana, L, et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS One 2015; 10: e0125614.Google Scholar
He, Z, Guo, JL, McBride, JD, et al. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 2018; 24: 2938.Google Scholar
Sopko, R, Golonzhka, O, Arndt, J, et al. Characterization of tau binding by gosuranemab. Neurobiol Dis 2020; 146: 105120.CrossRefGoogle ScholarPubMed

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