E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.

Protein bioconjugates have many criticala pplications, especially in the development of therapeutics. Consequently,t he design of novel methodologies to prepare protein bioconjugates is of great importance.H erein we presentt he development and optimization of an ovel strategy to prepare bioconjugates through ag enetically encoded [2+ +2+ +2] cycloaddition reaction. To do this, an ovel unnaturala minoa cid (UAA) containing ad ipropargyl amine functionality was synthesized and incorporated site specifically.T his UAA-containing protein was reactedw ith an alkyne-containing fluorophore to afford ac ovalentlyl inked, well-definedp rotein bioconjugate. This reaction is convenient with an optimized reactiont ime of just two hours at room temperature and yields as table, polysubstituted benzene ring. Overall, this work contributes an ew bioconjugation strategy to the growingt oolbox of reactions to develop protein bioconjugates, which have am yriad of applications.

Protein methyltransferases are vital to the epigenetic modification of gene expression. Thus, obtaining a better understanding of and control over the regulation of these crucial proteins has significant implications for the study and treatment of numerous diseases. One ideal mechanism of protein regulation is the specific installation of a photolabile-protecting group through the use of photocaged non-canonical amino acids. Consequently, PRMT1 was caged at a key tyrosine residue with a nitrobenzyl-protected Schultz amino acid to modulate protein function. Subsequent irradiation with UV light removes the caging group and restores normal methyltransferase activity, facilitating the spatial and temporal control of PRMT1 activity. Ultimately, this caged PRMT1 affords the ability to better understand the protein’s mechanism of action and potentially regulate the epigenetic impacts of this vital protein.