The development of BET BD1 selective chemical probes

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Abstract

Bromodomain and extra-terminal (BET) proteins have been implicated in a variety of oncological and immunological diseases. However, the domain specific functions of the individual domains of BET proteins, BD1 and BD2 still remain unclear. This work describes the design and development of a BET BD1 selective chemical probe that will have the required BD1 domain selectivity to probe the biological function of this BD1 domain. Initial data mining of an historic benzimidazole series was performed to provide insight into which vectors might provide BD1 selectivity. Four iterations of compounds have been synthesised which aim to take advantage of an amino acid point change between the BD1 and BD2 domains. Two ‘lead’ compounds have been identified, that maintain excellent potency and have the desired BD1 selectivity. These compounds also have the potential to be utilised in vivo. Consequently, these ‘lead’ compounds are superior to the initial benzimidazole compound from which this project was initiated; historically, production of a compound which is BD1 selective and could also be utilised in vivo was not successful. A hypothesis of how BET BD1 selectivity is obtained from these compounds is disclosed, and is rationalised with the aid of computational methods and X-ray crystallography.

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