7SS8

Human P300 complexed with a proline-based inhibitor

Summary for 7SS8

• Entry DOI: 10.2210/pdb7ss8/pdb
• Descriptor: Histone acetyltransferase p300, ZINC ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: histone acetyltransferase, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 66916.32

Authors

Shewchuk, L.M.,Reid, R.A. (deposition date: 2021-11-10, release date: 2022-11-09, Last modification date: 2023-10-18)

Primary citation

Tian, X.,Suarez, D.,Thomson, D.,Li, W.,King, E.A.,LaFrance, L.,Boehm, J.,Barton, L.,Di Marco, C.,Martyr, C.,Thalji, R.,Medina, J.,Knight, S.,Heerding, D.,Gao, E.,Nartey, E.,Cecconie, T.,Nixon, C.,Zhang, G.,Berrodin, T.J.,Phelps, C.,Patel, A.,Bai, X.,Lind, K.,Prabhu, N.,Messer, J.,Zhu, Z.,Shewchuk, L.,Reid, R.,Graves, A.P.,McHugh, C.,Mangatt, B.
Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening.
J.Med.Chem., 65:14391-14408, 2022

PubMed Abstract: 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 led to not only reduced clearance but also improved cMyc cellular potency.

PubMed: 36302181
DOI: 10.1021/acs.jmedchem.2c00670

Experimental method

X-RAY DIFFRACTION (2.15 Å)