title: Discovery of Novel Small Molecules that Activate Satellite Cell Proliferation and Enhance Repair of Damaged Muscle.
abstract: Skeletal muscle progenitor stem cells (referred to as satellite cells) represent the primary pool of stem cells in adult skeletal muscle responsible for the generation of new skeletal muscle in response to injury. Satellite cells derived from aged muscle display a significant reduction in regenerative capacity to form functional muscle. This decrease in functional recovery has been attributed to a decrease in proliferative capacity of satellite cells. Hence, agents that enhance the proliferative abilities of satellite cells may hold promise as therapies for a variety of pathological settings, including repair of injured muscle and age- or disease-associated muscle wasting. Through phenotypic screening of isolated murine satellite cells, we identified a series of 2,4-diaminopyrimidines (e.g., 2) that increased satellite cell proliferation. Importantly, compound 2 was effective in accelerating repair of damaged skeletal muscle in an in vivo mouse model of skeletal muscle injury. While these compounds were originally prepared as c-Jun N-terminal kinase 1 (JNK-1) inhibitors, structure-activity analyses indicated JNK-1 inhibition does not correlate with satellite cell activity. Screening against a broad panel of kinases did not result in identification of an obvious molecular target, so we conducted cell-based proteomics experiments in an attempt to identify the molecular target(s) responsible for the potentiation of the satellite cell proliferation. These data provide the foundation for future efforts to design improved small molecules as potential therapeutics for muscle repair and regeneration.
authors.affiliation: Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Billin
authors.affiliation: Cellzome AG , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bantscheff
authors.affiliation: Cellzome AG , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.affiliation: Cellzome AG , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Ghidelli-Disse
authors.affiliation: Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Holt
authors.affiliation: Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Henning F
authors.initials: HF
authors.lastname: Kramer
authors.affiliation: Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: McDougal
authors.affiliation: Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Smalley
authors.affiliation: Department of Chemical Biology, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Carrow I
authors.initials: CI
authors.lastname: Wells
authors.affiliation: Department of Chemical Biology, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Zuercher
authors.affiliation: Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Brad R
authors.initials: BR
authors.lastname: Henke
mesh_terms: D016475:3T3 Cells; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000293:injuries / Q000502:physiology*; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D011743:Pyrimidines; C017205:2,4-diaminopyrimidine