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Barsyte, D.

Publications and source records attributed to Barsyte, D..

2 recordsLinked to original sources
bioRxiv2020

Rational Design and Synthesis of Selective PRMT4 Inhibitors: a New Chemotype for Development of Cancer Therapeutics

Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates arginine residues of histone H3 and non-histone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and potentially therapeutics. While several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Here, we report the structure-based design of a new class of alanine containing 3-arylindoles as potent and selective PRMT4 inhibitors and describe key structure activity relationships for this class of compounds.

pharmacology and toxicology↗
bioRxiv2019

A Chemical Probe of CARM1 Alters Epigenetic Plasticity against Breast Cancer Cell Invasion

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

biochemistry↗