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 |
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| Rok vydání: | 2020 |
| Předmět: |
Indole test
Histone Acetyltransferases biology 010405 organic chemistry Chemistry Organic Chemistry Neurodegeneration Histone acetyltransferase Pharmacology medicine.disease 01 natural sciences Biochemistry 0104 chemical sciences Bioavailability 010404 medicinal & biomolecular chemistry Drug Discovery biology.protein medicine Potency CREB-binding protein EP300 |
| 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 |
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