WITHDRAWN: ActRIIB small molecule inhibitor 2-67 ameliorates muscle atrophy in cancer cachexia by inhibiting the myostatin/Smad pathway

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.