title: Fragment-based discovery of nonpeptidic BACE-1 inhibitors using tethering.
abstract: BACE-1 (beta-site amyloid precursor protein cleaving enzyme), a prominent target in Alzheimer's disease drug discovery efforts, was surveyed using Tethering technology to discover small molecule fragment ligands that bind to the enzyme active site. Screens of a library of >15000 thiol-containing fragments versus a panel of BACE-1 active site cysteine mutants under redox-controlled conditions revealed several novel amine-containing fragments that could be selectively captured by subsets of the tethering sites. For one such hit class, defined by a central aminobenzylpiperidine (ABP) moiety, X-ray crystal structures of BACE mutant-disulfide conjugates revealed that the fragment bound by engaging both catalytic aspartates with hydrogen bonds. The affinities of ABP fragments were improved by structure-guided chemistry, first for conjugation as thiol-containing fragments and then for stand-alone, noncovalent inhibition of wild-type (WT) BACE-1 activity. Crystallography confirmed that the inhibitors bound in exactly the same mode as the disulfide-conjugated fragments that were originally selected from the screen. The ABP ligands represent a new type of nonpeptidic BACE-1 inhibitor motif that has not been described in the aspartyl protease literature and may serve as a starting point for the development of BACE-1-directed Alzheimer's disease therapeutics.
authors.affiliation: Department of Chemistry, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard,South San Francisco, California 94080, USA. wyang@eigerbio.com
authors.forename: Wenjin
authors.initials: W
authors.lastname: Yang
authors.forename: Raymond V
authors.initials: RV
authors.lastname: Fucini
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Fahr
authors.forename: Mike
authors.initials: M
authors.lastname: Randal
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lind
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Lam
authors.forename: Wanli
authors.initials: W
authors.lastname: Lu
authors.forename: Yafan
authors.initials: Y
authors.lastname: Lu
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cary
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Romanowski
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Allison
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: David M
authors.initials: DM
authors.lastname: Penny
authors.forename: Phuongly
authors.initials: P
authors.lastname: Pham
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.forename: Anila E
authors.initials: AE
authors.lastname: Thomas
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Wilkinson
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Jacobs
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Ballinger
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055162:Biocatalysis; D020134:Catalytic Domain; D003545:Cysteine; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D010455:Peptides; D010880:Piperidines; D053829:Amyloid Precursor Protein Secretases; D003545:Cysteine