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Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.

Keylor MH, Gulati A, Kattar SD, Johnson RE, Chau RW, Margrey KA, Ardolino MJ, Zarate C, Poremba KE, Simov V, Morriello GJ, Acton JJ, Pio B, Yan X, Palte RL, McMinn SE, Nogle L, Lesburg CA, Adpressa D, Lin S, Neelamkavil S, Liu P, Su J, Hegde LG, Woodhouse JD, Faltus R, Xiong T, Ciaccio PJ, Piesvaux J, Otte KM, Wood HB, Kennedy ME, Bennett DJ, DiMauro EF, Fell MJ, Fuller PH
J Med Chem 65 838-856 (2022)
Related entries: 7suf, 7sug, 7suh, 7sui

Cited: 7 times
EuropePMC logo PMID: 34967623

Abstract

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds

Reviews citing this publication (2)

  1. Structural Insights and Development of LRRK2 Inhibitors for Parkinson's Disease in the Last Decade. Thakur G, Kumar V, Lee KW, Won C. Genes (Basel) 13 1426 (2022)
  2. Targeting caspase-2 interactions with tau in Alzheimer's disease and related dementias. Pockes S, Walters MA, Ashe KH. Transl Res 254 34-40 (2023)

Articles citing this publication (5)

  1. Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2. Liu X, Kalogeropulou AF, Domingos S, Makukhin N, Nirujogi RS, Singh F, Shpiro N, Saalfrank A, Sammler E, Ganley IG, Moreira R, Alessi DR, Ciulli A. J Am Chem Soc 144 16930-16952 (2022)
  2. Capturing Differences in the Regulation of LRRK2 Dynamics and Conformational States by Small Molecule Kinase Inhibitors. Weng JH, Ma W, Wu J, Sharma PK, Silletti S, McCammon JA, Taylor S. ACS Chem Biol 18 810-821 (2023)
  3. Computing the relative binding affinity of ligands based on a pairwise binding comparison network. Yu J, Li Z, Chen G, Kong X, Hu J, Wang D, Cao D, Li Y, Huo R, Wang G, Liu X, Jiang H, Li X, Luo X, Zheng M. Nat Comput Sci 3 860-872 (2023)
  4. Development of mutation-selective LRRK2 kinase inhibitors as precision medicine for Parkinson's disease and other diseases for which carriers are at increased risk. Lesniak RK, Nichols RJ, Montine TJ. Front Neurol 13 1016040 (2022)
  5. Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2. Park H, Kim T, Kim K, Jang A, Hong S. Int J Mol Sci 23 12825 (2022)


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