Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening

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.