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

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.

SUBMITTER: Wilson JE

PROVIDER: S-EPMC7294707 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Wilson Jonathan E JE Patel Gaurav G Patel Chirag C Brucelle Francois F Huhn Annissa A Gardberg Anna S AS Poy Florence F Cantone Nico N Bommi-Reddy Archana A Sims Robert J RJ Cummings Richard T RT Levell Julian R JR

ACS medicinal chemistry letters 20200423 6

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 ...[more]

PMID: 32551019

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