title: Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling.
abstract: Mutations in the genetic sequence of leucine-rich repeat kinase 2 (LRRK2) have been linked to increased LRRK2 activity and risk for the development of Parkinson's disease (PD). Potent and selective small molecules capable of inhibiting the kinase activity of LRRK2 will be important tools for establishing a link between the kinase activity of LRRK2 and PD. In the absence of LRRK2 kinase domain crystal structures, a LRRK2 homology model was developed that provided robust guidance in the hit-to-lead optimization of small molecule LRRK2 inhibitors. Through a combination of molecular modeling, sequence analysis, and matched molecular pair (MMP) activity cliff analysis, a potent and selective lead inhibitor was discovered. The selectivity of this compound could be understood using the LRRK2 homology model, and application of this learning to a series of 2,4-diaminopyrimidine inhibitors in a scaffold hopping exercise led to the identification of highly potent and selective LRRK2 inhibitors that were also brain penetrable.
authors.affiliation: Discovery Chemistry Department, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States. chen.huifen@gene.com
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Chan
authors.forename: Jason
authors.initials: J
authors.lastname: Drummond
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Estrada
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Moffat
authors.forename: Daniel
authors.initials: D
authors.lastname: Shore
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.forename: Thuy
authors.initials: T
authors.lastname: Tran
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Burdick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D019295:Computational Biology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009025:Morpholines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010539:Permeability; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D009025:Morpholines; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; D053614:Janus Kinase 2; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases