2. Academic Validation
  3. 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.
PMID: 33872011 DOI: 10.1021/acs.jmedchem.0c02232
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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