title: Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.
abstract: We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Axten
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Romeril
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Arthur
authors.initials: A
authors.lastname: Shu
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ralph
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Jesús R
authors.initials: JR
authors.lastname: Medina
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: William Hoi Hong
authors.initials: WH
authors.lastname: Li
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Seth W
authors.initials: SW
authors.lastname: Grant
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Minthorn
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mencken
authors.affiliation: Screening and Compound Profiling, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Gaul
authors.affiliation: Screening and Compound Profiling, GlaxoSmithKline Research and Development , Research Triangle Park, North Carolina 27713, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Goetz
authors.affiliation: Screening and Compound Profiling, GlaxoSmithKline Research and Development , Research Triangle Park, North Carolina 27713, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stanley
authors.affiliation: Biomolecular Structure, Computational and Structural Chemistry, GlaxoSmithKline Research and Development , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Annie M
authors.initials: AM
authors.lastname: Hassell
authors.affiliation: Biomolecular Structure, Computational and Structural Chemistry, GlaxoSmithKline Research and Development , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Gampe
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Charity
authors.initials: C
authors.lastname: Atkins
authors.affiliation: Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development , Collegeville, Pennsylvania 19426, United States.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
keywords: PERK; UPR; fluorine interaction; kinase; lead optimization; structure−activity relationship