Bone morphogenetic protein (BMP) signaling contributes to acute kidney injury (AKI), a common disease without adequate treatment options. In this issue of Cell Chemical Biology, Larraufie, Gao and colleagues (Larraufie et al., 2021) show that FKBP12 inhibition can be a target for treatment of AKI via activation of BMP signaling.

Use of hypoxia-activated prodrugs has emerged as a strategy for selectively targeting tumors in hypoxic conditions harboring reductive environments. In this issue of Cell Chemical Biology, Skwarska et al. (2021) report a hypoxia-activated prodrug targeting histone deacetylases (lysine deacetylases, KDACs) selectively over normoxic cells with activity in an animal model.

In this issue of Cell Chemical Biology, Libardo et al. (2021) identify prodrugs that kill Mtb through poisoning of its L-tryptophan biosynthetic pathway. Determination of the mechanisms of resistance evolved by the bacterium highlights the importance of metabolic flux modulation in TB drug resistance.

Growing evidence implicates a vital role for TPC2/Ca2+ signaling in pathophysiological processes attributed to cancer, raising questions regarding the utility of TPC2 as a cancer therapeutic target. In this issue of Cell Chemical Biology, Müller et al. (2021) develop TPC2 inhibitors, SG005 and SG-094, exhibiting anti-tumor effects with potential translational relevance.

In this issue of Cell Chemical Biology, Chatrikhi et al. (2021) identify a small molecule that enhances U2AF2 association with RNA to block pre-mRNA splicing during early stages of spliceosome assembly. This provides a mechanism of splicing inhibition and a molecular tool for elucidating intron recognition and spliceosome assembly.

Unbiased profiling approaches are powerful tools for small-molecule target or mode-of-action deconvolution as they generate a holistic view of the bioactivity space. This is particularly important for non-protein targets that are difficult to identify with commonly applied target identification methods. Thereby, unbiased profiling can enable identification of novel bioactivity even for annotated compounds