2. Academic Validation
  3. Generation of BT-Amide, a Bone-Targeted Pyk2 Inhibitor, Effective via Oral Administration, for the Prevention of Glucocorticoid-Induced Bone Loss

Generation of BT-Amide, a Bone-Targeted Pyk2 Inhibitor, Effective via Oral Administration, for the Prevention of Glucocorticoid-Induced Bone Loss

  • J Med Chem. 2024 Nov 28;67(22):20708-20720. doi: 10.1021/acs.jmedchem.4c02539.
Xiuqi Wang 1,  Amy Y Sato 2,  Silvia Marino 2,  Nisreen Akel 2,  Gunnar Boysen 3,  Alexei G Basnakian 4 5,  Teresita M Bellido 2 5 6,  Hong-Yu Li 7 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
  • 2 Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
  • 3 Department of Environmental Health Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
  • 4 Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
  • 5 Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, United States.
  • 6 Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
  • 7 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
  • 8 Department of Pharmacology, School of Medicine, The University of Texas Health San Antonio, San Antonio, Texas 78229, United States.
PMID: 39540576 DOI: 10.1021/acs.jmedchem.4c02539
Abstract

Glucocorticoid-induced osteoporosis (GIOP) is the leading cause of iatrogenic osteoporosis due to the widespread clinical use of glucocorticoids (GC) as immunosuppressants. Previous research identified the proline-rich tyrosine kinase 2, Pyk2, as a critical mediator of GC-induced bone loss, and that blocking Pyk2 could protect the skeleton from adverse GC actions. However, systemic administration of current Pyk2 inhibitors causes harmful side effects, such as skin lesions. To address this, we developed bone-targeted (BT) Pyk2 inhibitors by conjugating them with bisphosphonates (BP), ensuring adherence to the bone matrix and reducing impact on noncalcified tissues. We synthesized BT-Amide by linking a derivative of TAE-226, a Pyk2 Inhibitor, with alendronic acid. Oral administration (gavage) of BT-Amide prevented GC-induced bone loss in mice without causing skin lesions, or elevation of any organ toxicity markers. These findings introduce BT-Amide as the first orally effective bone-targeted Pyk2 Inhibitor for preventing GC-induced bone loss while minimizing off-target effects.

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