A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion.

Abstract

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here <b>SKI-73</b> (<b>6a</b> in this work) is presented as a CARM1 chemical probe with pro-drug properties. <b>SKI-73</b> (<b>6a</b>) can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for several days. These compounds were characterized for their potency, selectivity, modes of <b>action</b>, and on-target engagement. <b>SKI-73</b> (<b>6a</b>) recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the <b>SKI-73</b>(<b>6a</b>)-associated reduction of invasiveness acts by altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, <b>SKI-73</b> (<b>6a</b>) and CARM1 knockout alter the epigenetic plasticity with remarkable difference, suggesting distinct modes of action for small-molecule and genetic perturbations. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.