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New Therapeutics Targeting Heart Failure: Development of GRK2 Selective Inhibitors
Author(s) -
Homan Kristoff T,
Thal David M,
Wu Emily,
Chen Jun,
Sklar Larry,
Tesmer John JG
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.665.8
Subject(s) - g protein coupled receptor kinase , beta adrenergic receptor kinase , g protein coupled receptor , pharmacology , heart failure , receptor , in vivo , phosphorylation , drug discovery , chemistry , medicine , biology , biochemistry , microbiology and biotechnology
Heart failure is a leading cause of death in adults throughout the world. One of the defining characteristics of heart failure is dysregulation of G protein‐coupled receptor (GPCR) signaling, namely that mediated by the β‐adrenergic receptors (βARs). Prolonged stimulation of βARs results in receptor desensitization, which is initiated through phosphorylation by G protein‐coupled receptor kinases (GRKs). It has been demonstrated that inhibition of one of these GRKs, GRK2, improves prognosis in heart failure through increased cardiac performance. Given the therapeutic potential of inhibiting GRK2, considerable effort has been devoted towards developing selective inhibitors. In this work, high‐throughput screening methods were used to identify potential GRK2 inhibitors. One set of related compounds has been identified as potent inhibitors of GRK2 for which structure‐activity relationships are being elucidated. Another inhibitor is a previously approved FDA drug which demonstrated high selectivity for GRK2 in vitro and was efficacious in vivo . Support was provided by NIH grants HL086865, HL071818, and MH089378.