2. Academic Validation
  3. Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL

Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL

  • Org Biomol Chem. 2022 May 18;20(19):4021-4029. doi: 10.1039/d2ob00609j.
Anthony K Edmonds 1,  Catherine S Oakes 2,  Storm Hassell-Hart 1,  Didier Bruyère 2,  Graham J Tizzard 3,  Simon J Coles 3,  Robert Felix 2,  Hannah J Maple 2,  Graham P Marsh 2,  John Spencer 1 4
Affiliations

Affiliations

  • 1 Chemistry Department, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QJ, UK. j.spencer@sussex.ac.uk.
  • 2 Bio-Techne (Tocris), The Watkins Building, Atlantic Road, Bristol, BS11 9QD, UK.
  • 3 National Crystallography Service, School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK.
  • 4 Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QJ, UK.
PMID: 35506991 DOI: 10.1039/d2ob00609j
Abstract

ISOX-DUAL is a dual inhibitor of CBP/p300 (IC50 = 0.65 μM) and BRD4 (IC50 = 1.5 μM) bromodomains, and a useful chemical probe for epigenetic research. Aspects of the published synthetic route to this compound and its analogues are small-scale, poor-yielding or simply unamenable to scale-up without optimization. Herein we describe the development of a refined synthesis that circumvents the challenges of the original report, with notable improvements to several of the key synthetic transformations. Moreover, a general Suzuki Miyaura protocol for the late stage installation of alternative dimethyl-isoxazole acetyl-lysine (KAc) binding motifs is presented.

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