ActRIIB small molecule inhibitor 2–67 ameliorates muscle atrophy in cancer cachexia by inhibiting the myostatin/Smad pathway

Abstract

Muscle atrophy is one of the major clinical features of cancer cachexia, a multifactorial complex syndrome complicated by malignancy that remains a major challenge in clinical treatment. The myostatin/Smad signaling pathway, an important pathway for muscle protein degradation, is aberrantly activated in muscle atrophy mainly by the binding of myostatin to ActRIIB kinase. Here, a series of novel small molecule compounds were screened using a molecule-level screening model for ActRIIB kinase inhibitory activity and a cell-level screening model for C26 tumor cell conditioned medium-induced C2C12 myotube atrophy. Among the compounds, compound 2–67 exhibited significant ActRIIB kinase inhibition and myotubular atrophy alleviation effects. Furthermore, 2–67 dose-dependently attenuated myocyte atrophy induced by cachexic tumor cell conditioned medium or myostatin by inhibiting the activation of the myostatin/Smad signaling pathway in C2C12 myotubes. In a C26 tumor-bearing mouse cancer cachexia model, 2–67 treatment effectively alleviated cancer cachexia symptoms. 2–67 ameliorated the loss in body weight, improved appetite, alleviated muscle loss, and preserved muscle grip strength. 2–67 also inhibited the myostatin/Smad signaling pathway in muscle tissues in cancer cachexia mice. Therefore, novel small molecule inhibitors of ActRIIB kinase may be a new option for the treatment of cancer cachexia-induced muscle atrophy, and the present work provides an important reference for the subsequent development and application of related inhibitors.