Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor

Autor: Anna S. Gardberg, Francois Brucelle, Robert J. Sims, Nico Cantone, Richard T. Cummings, Florence Poy, Archana Bommi-Reddy, Julian Levell, Jonathan E. Wilson, Chirag Patel, Annissa J. Huhn, Gaurav Patel
Rok vydání: 2020
Předmět:
Zdroj: ACS Med Chem Lett
ISSN: 1948-5875
Popis: [Image: see text] 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.
Databáze: OpenAIRE