Identification of first-in-class small molecule potential inhibitor of GDF15

Abstract

BackgroundGrowth Differentiation Factor 15 (GDF15), a mitokine implicated in stress response, has been associated with numerous diseases, particularly cancer cachexia. Many approaches, including monoclonal antibodies and peptide antagonists, have been implemented to inhibit GDF15 activity. It is currently unknown whether it is possible to inhibit GDF15 using small organic molecules (SOMs). MethodsA structure-based in silico screening workflow of a curated compound library was implemented to identify SOMs capable of binding to the monomeric or dimeric form of GDF15. The three top-ranking SOMs of each group were then tested in vitro on normal and cancer cells. ResultsAmong all tested SOMs, dioxoimidazolidin derivative named SOM D resulted capable of inhibiting GDF15 dimer formation and decreasing binding to GFRAL. Furthermore, it was found to be devoid of acute cytotoxicity both in normal cells (dermal fibroblasts, DFs) and tumor cells (OV90), to significantly slow proliferation and modify the expression of genes involved in GDF15 signaling or in cell cycle and senescence in OV90, but not in DFs. Interestingly, simultaneous treatment with SOMs and doxorubicin (doxo) failed in arresting the cell cycle compared to doxo alone. ConclusionsThe in silico screening has proven effective in identifying SOMs putatively capable of inhibiting GDF15, among which SOM D appears the most promising. Further characterizations will be necessary to better understand the exact mechanisms of action. Furthermore, the observation that SOMs have an opposite effect on proliferation in cancer versus normal cellular context suggests a dual role in cell-cycle control in presence of cancer aberration.