No abstract

The histone acetyltransferases, CREB binding protein (CBP) and EP300, are master transcriptional co-regulators that have been implicated in numerous diseases, such as cancer, inflammatory disorders, and neurodegeneration. A novel, highly potent, orally bioavailable EP300/CBP histone acetyltransferase (HAT) inhibitor, CPI-1612 or 17, was developed from the lead compound 3. Replacement of the indole scaffold of 3 with the aminopyridine scaffold of 17 led to improvements in potency, solubility, and bioavailability. These characteristics resulted in a 20-fold lower efficacious dose for 17 relative to lead 3 in a JEKO-1 tumor mouse xenograft study.

A straightforward process to aminate pyridines and diazines is presented by reacting phosphonium salt derivatives with sodium azide. The iminophosphorane products are versatile precursors to several nitrogen-containing functional groups, and the process can be applied to building block heterocycles, drug-like fragments and for late-stage functionalization of complex pharmaceuticals. Appealing features of this strategy include using C–H bonds as precursors, precise regioselectivity, and a distinct scope from other amination methods, particularly those relying on halogenated azaarenes.

A highly efficient method of visible light mediated Ni(II)-catalyzed photoredox N-arylation of Cbz-amines/Bocamines with aryl electrophiles at room temperature is reported. The methodology provides a common access to a wide variety of N-aromatic and N-heteroaromatic carbamate products that find use in the synthesis of several biologically active molecules and provides a distinct advantage over traditional palladium-catalyzed Buchwald reaction.

EP300 and CBP (KAT3A/3B) are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription through the acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high‐throughput screen of 191 000 compounds searching for EP300/CBP histone acetyltransferase (HAT) inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including X‐ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, including two classes not previously described. The profiles of an example of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA‐competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of HAT inhibitors.