科研之友
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摘要
TGF-beta 1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-beta 1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-beta 1induced epithelial-mesenchymal transition without immediate TGF-beta 1 receptor (T beta R) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-beta 1 responses (IC50 similar to 50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits T beta RI kinase. Combined inhibition of LOXL2 and T beta RI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting T beta RI kinase in LOXL2-expressing cells.
