Structure-guided identification of small molecules potentially able to modulate GDF15 activity.

Growth Differentiation Factor 15 (GDF15) has been associated with different pathological conditions, including cancer cachexia. Various strategies, such as monoclonal antibodies and peptide antagonists, have been developed to inhibit GDF15 activity; however, it is currently unknown whether using small organic molecules (SOMs) can effectively target GDF15. Here, we implemented a structure-based in silico screening workflow using a curated compound library to identify SOMs with potential binding affinity for GDF15. The top-ranking SOMs predicted to interact with either the monomeric or dimeric forms of GDF15 were then tested in vitro in acellular systems, as well as in normal (dermal fibroblasts, DFs) and cancer (ovarian, OV90) cells characterized by low or high GDF15 expression levels, respectively. Among the tested SOMs, dioxoimidazolidin derivative (named SOM D) emerged as particularly promising, as resulted capable of disturbing GDF15 dimer stability and GDF15-GFRAL interaction. Furthermore, SOM D significantly modulated genes and proteins recognized as downstream of GDF15 signaling, such as IL-6 and NF-κB, particularly in OV90 cells, but not in DFs. Overall, these results support the idea that GDF15 activity could be modulated through SOMs and warrant further structure-activity optimization and quantitative target-engagement studies to assess the therapeutic potential of these scaffolds as GDF15 inhibitors.