title: Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept.
abstract: Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.
authors.affiliation: Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Therapeutic Discovery-Protein Technologies, ∥Department of Metabolic Disorders, ⊥Department of Pharmacokinetics and Drug Metabolism, #Department of Pathology, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Kate S
authors.initials: KS
authors.lastname: Ashton
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.forename: Marian C
authors.initials: MC
authors.lastname: Bryan
authors.forename: Marion C
authors.initials: MC
authors.lastname: Bryan
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Michelle
authors.initials: M
authors.lastname: Chen
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.forename: Michael
authors.initials: M
authors.lastname: Croghan
authors.forename: Rod
authors.initials: R
authors.lastname: Cupples
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Joan
authors.initials: J
authors.lastname: Helmering
authors.forename: Steve R
authors.initials: SR
authors.lastname: Jordan
authors.forename: Robert J M
authors.initials: RJ
authors.lastname: Kurzeja
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.forename: Steve F
authors.initials: SF
authors.lastname: Poon
authors.forename: Glenn
authors.initials: G
authors.lastname: Sivits
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Van
authors.forename: Steve L
authors.initials: SL
authors.lastname: Vonderfecht
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005941:Glucokinase / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D010879:Piperazines / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D021381:Protein Transport; D051381:Rats; D011924:Rats, Zucker; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology
chemical_list: C585747:1,1,1-trifluoro-2-(4-(2-((3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D010879:Piperazines; D013449:Sulfonamides; C080906:glucokinase regulatory protein; D005941:Glucokinase