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.

中文翻译：

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BT-Amide 的产生，一种骨靶向 Pyk2 抑制剂，通过口服有效，用于预防糖皮质激素诱导的骨流失


糖皮质激素诱导的骨质疏松症 （GIOP） 是医源性骨质疏松症的主要原因，因为临床上广泛使用糖皮质激素 （GC） 作为免疫抑制剂。先前的研究确定富含脯氨酸的酪氨酸激酶 2 Pyk2 是 GC 诱导的骨质流失的关键介质，阻断 Pyk2 可以保护骨骼免受不良 GC 作用。然而，当前 Pyk2 抑制剂的全身给药会引起有害的副作用，例如皮肤损伤。为了解决这个问题，我们通过将骨靶向 （BT） Pyk2 抑制剂与双膦酸盐 （BP） 偶联来开发，确保粘附在骨基质上并减少对非钙化组织的影响。我们通过将 Pyk2 抑制剂 TAE-226 的衍生物与阿仑膦酸连接合成了 BT-Amide。口服 BT-Amide 给药（灌胃）可防止 GC 诱导的小鼠骨质流失，而不会引起皮肤损伤或任何器官毒性标志物的升高。这些发现介绍了 BT-Amide 作为第一个口服有效的骨靶向 Pyk2 抑制剂，用于防止 GC 诱导的骨流失，同时最大限度地减少脱靶效应。