1. Academic Validation
  2. Development of Dimethylisoxazole-Attached Imidazo[1,2- a]pyridines as Potent and Selective CBP/P300 Inhibitors

Development of Dimethylisoxazole-Attached Imidazo[1,2- a]pyridines as Potent and Selective CBP/P300 Inhibitors

  • J Med Chem. 2021 May 13;64(9):5787-5801. doi: 10.1021/acs.jmedchem.0c02232.
Alex Muthengi 1 Virangika K Wimalasena 2 Hailemichael O Yosief 1 Melissa J Bikowitz 3 4 Logan H Sigua 2 Tingjian Wang 2 Deyao Li 2 Zied Gaieb 5 Gagan Dhawan 6 Shuai Liu 1 Jon Erickson 1 Rommie E Amaro 5 Ernst Schönbrunn 3 4 Jun Qi 2 7 Wei Zhang 1
Affiliations

Affiliations

  • 1 Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, Massachusetts 02125, United States.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
  • 3 Drug Discovery Department, Moffit Cancer Center, Tampa, Florida 33612, United States.
  • 4 Department of Molecular Medicine, USF Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • 5 Department of Chemistry & Biochemistry, University of California, San Diego, 9500 Gilman Dr, LA Jolla, California 92093, United States.
  • 6 Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi, Delhi, New Delhi 110019, India.
  • 7 Department of Medicine, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, United States.
Abstract

The use of epigenetic bromodomain inhibitors as Anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound 23, CBP IC50 72 nM and bromodomain 4, BRD4 IC50 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains.

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