Design, synthesis and biological evaluation of coumarin-containing 2,4-diphenylpyrimidine derivatives as novel focal adhesion kinase inhibitors for treatment of non-small cell lung cancer

Article

Author: Li, Jiayi ; Jin, Xin ; Huang, Hanxue ; Zhang, Jinlin ; Lei, Mengrong ; Kang, Fenghua ; Liu, Zhaoqian ; Yu, Geng ; Liu, Junyan

A series of hybrids (8a-h and 11a-h) containing 2,4-diphenylpyrimidine scaffold and coumarin moiety were designed and synthesized as novel focal adhesion kinase (FAK) inhibitors for the intervention of non-small-cell lung cancer (NSCLC). Most compounds effectively suppressed the proliferative of NSCLC cells, and compound 8a was identified as the most active compound with IC₅₀ value of 0.28 μM in H1299 cells, superior to TAE226 (IC₅₀ = 2.28 μM). In addition, 8a was also found to inhibit the invasion and migration of NSCLC cells. Furthermore, 8a exhibited potent kinase inhibitory activity of FAK (IC₅₀ = 4.968 nM) with a considerable selectivity profile against various kinase families, subsequently resulting in cell cycle arrest, apoptosis- inducing as well as the decrease of MMP-2 and MMP-9 expression in H1299 cells dose-dependently. Moreover, 8a was relatively safe to mice and inhibited the growth of implanted NSCLC tumors more potently than TAE226 in mice. Therefore, 8a may be a promising candidate for the treatment of NSCLC.

01 Apr 2025·European Journal of Medicinal Chemistry

Discovery of 2,4-diaminopyrimidine derivatives as potent inhibitors of FAK capable of activating the Hippo pathway for the treatment of esophageal squamous cell carcinoma

Article

Author: Zhang, Sai-Yang ; Wang, Xiao ; Li, Yin-Ru ; Niu, Jin-Bo ; Song, Jian ; Wu, Ji

In this work, we report the discovery of 2,4-diaminopyrimidine derivatives bearing a urea moiety as FAK inhibitors capable of activating the Hippo pathway in Esophageal Squamous Cell Carcinoma (ESCC). Extensive structure-activity relationship studies were conducted based on the lead FAK inhibitor TAE-226 to enhance the inhibitory potency, and the most potent compound 8b (MY-1576) as a FAK inhibitor ultimately was identified. Compound MY-1576 exhibited potent FAK inhibitory activity, in vitro anticancer activities, and acceptable PK properties. Notably, MY-1576 could activate the Hippo pathway, resulting in impeding YAP/TAZ regulation. MY-1576 also effectively suppressed the tumor growth in the KYSE30 xenograft mouse models with good safety profiles, and potently down-regulated the autophosphorylation of FAK and the levels of YAP/TAZ in vivo. Taken together, these results indicate that MY-1576, functioning as a FAK inhibitor capable of activating the Hippo pathway, is a promising candidate against ESCC.

28 Nov 2024·Journal of Medicinal Chemistry

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

Article

Author: Wang, Xiuqi ; Basnakian, Alexei G. ; Marino, Silvia ; Sato, Amy Y. ; Bellido, Teresita M. ; Li, Hong-Yu ; Boysen, Gunnar ; Akel, Nisreen

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.

100 Deals associated with TAE-226

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	Switzerland	Novartis AG	-
Neoplasms	Discovery	Austria	Novartis AG	-

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