title: Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β.
abstract: Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure-activity relationship, and finally lead to the synthesis of a more potent compound.
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Yikai
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Wach
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sheehan
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
authors.forename: Chenyang
authors.initials: C
authors.lastname: Zhan
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Harris
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, United States; Department of Neurology & Psychiatry, Harvard Medical School and Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Bishop
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, United States; Department of Neurology & Psychiatry, Harvard Medical School and Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ramek
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Kayla N
authors.initials: KN
authors.lastname: Berry
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Conor
authors.initials: C
authors.lastname: O'Herin
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Angela N
authors.initials: AN
authors.lastname: Koehler
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Alvin W
authors.initials: AW
authors.lastname: Hung
authors.affiliation: Chemical Biology Program, The Broad Institute of Harvard and MIT , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Damian W
authors.initials: DW
authors.lastname: Young
keywords: Diversity oriented synthesis; GSK3β; fragment growing; fragment-based drug discovery