2. Academic Validation
  3. Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor

Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor

  • Bioorg Med Chem Lett. 2020 Dec 1;30(23):127602. doi: 10.1016/j.bmcl.2020.127602.
Guozhang Xu 1,  Michael D Gaul 2,  Zhijie Liu 2,  Renee L DesJarlais 2,  Jenson Qi 3,  Weixue Wang 2,  Daniel Krosky 2,  Ioanna Petrounia 2,  Cynthia M Milligan 2,  An Hermans 4,  Hua-Rong Lu 4,  Devine Zheng Huang 3,  June Zhi Xu 3,  John C Spurlino 2
Affiliations

Affiliations

  • 1 Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States. Electronic address: [email protected].
  • 2 Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States.
  • 3 Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, United States.
  • 4 Discovery Sciences, Janssen Research & Development, LLC, Turnhoutseweg 30, 2340 Beerse, Belgium.
PMID: 33038544 DOI: 10.1016/j.bmcl.2020.127602
Abstract

G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of β-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting Enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.

Keywords

Cardiomyocytes; GRK2 inhibitor; Heart failure; Molecular modelling; Structure-based drug design; β-Adrenergic receptor.

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