EML631

Suppl Fig 8b of the cited publication (Bae et al Nat. Chem. Biol. doi:10.1038/nchembio.2377) indicates that enhanced inhibition of SPIN1-regulated gene expression is observed at EML631 concentrations higher than 10uM (data for 20uM is shown in Suppl Fig 8b); thus, users may be tempted to investigate EML631 at concentrations higher than 10uM. However, there is insufficient data to substantiate selectivity at higher concentrations. In addition EML631 is a lipophilic tribasic molecule; such molecules are commonly prone to lysosomal trapping which may result in off-target effects, especially at high concentrations (See Black et al Chembiochem. 2006 Oct;7(10):1525-35. doi:10.1002/cbic.200600149). Users of EML631 should also be aware that the aminal function that is associated with the less basic of the three basic centres may be chemically unstable resulting in aminal hydrolysis to a phenol; the biological properties of the phenol have not been characterised. Use of SPIN1 inhibitor MS31 (Xiong et al: https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00522) and its negative control MS31N alongside EML631 may be useful to build confidence that observed cellular phenotypes are SPIN1-driven.