Discovery of the first-in-class chemical probe for the Spindlin1 methyl-lysine reader domain

Histone post-translational modifications (PTMs) have been proposed to constitute a “histone code”, which helps to organize genetic information at the chromatin level, and play a pivotal role in gene expression, cell differentiation, and development. During the past decade, a wealth of “reader” modules have been characterized for histone PTM recognition, that function in a histone type- and site-specific manner. In particular, the detection of methylated histone tail lysine residues by Tudor domains plays important roles in epigenetic control of gene expression and DNA damage response. Among them, Spindlin1 (SPIN1, Figure 1) is a protein of the SPIN/SSTY family implicated in the regulation of gametogenesis. Furthermore, its overexpression perturbs the cell cycle, induces chromosome instability, and leads to tumorigenesis,[4-6] even if the molecular mechanisms remain poorly understood. Being interested in the development of novel small molecule modulators of epigenetic targets, here we report the identification of the first, specific inhibitor of Spindlin1. Thus, our work paves the way for future progress in Spindlin1 biology and its therapeutic applications.