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DRUG DISCOVERY

Choosing your druggability battle

Nature Chemical Biology volume 15, pages 652–653 (2019)Cite this article

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The advent of PROTACs that degrade the entire protein target rather than simply inhibiting it bring druggable yet apparently non-functional binding sites into play for medicinal chemists to do their work.

Proteins frequently contain multiple domains that are tasked with a multiplicity of functions. The reductionist approach of drug discovery may focus on targeting a catalytic domain or a specific binding site that is perceived to be druggable when in search of functional inhibition of the protein target. The first reports of druggable binding sites and small-molecule ligands for the BET subfamily of bromodomain-containing proteins triggered significant interest in the remaining members of this acetyllysine reader family1. The recognition of histone lysine acetylation by bromodomains plays a role in protein–histone association during chromatin remodeling and can ultimately affect protein transcription2. Bromodomain-containing SMARCA proteins can be found as subunits within SWI–SNF complexes which are responsible for nucleosome remodeling3. The SMARCA proteins are multidomain proteins that play multiple roles in addition to the acetyllysine reading function performed by the bromodomain. In 2015, the use of RNAi and the identification of small-molecule ligands for the SMARCA and polybromo bromodomain family (so-called subfamily VIII of the bromodomain-containing proteins) showed that the phenotypes identified based on the knockdown of SMARCA2 through its synthetically lethal relationship with SMARCA4 were actually driven by the ATPase domain activity and not by the role of the bromodomain found within the same protein4. SMARCA2/4 bromodomain small-molecule inhibitors did not replicate the RNAi-derived effects, and the hope that these highly druggable bromodomains would yield exciting phenotypes was dashed. At the time, the compelling biology derived from RNAi knockdown drove many laboratories to consider a drug discovery program against the significantly more challenging ATPase domain found within the SMARCA proteins5. These challenges were perceived to be around the small-molecule druggability and selectivity potential for such domains. The ‘SMARCA function inhibition dilemma’ for drug discovery could be summed up by the realization that the target contained a druggable but non-functional bromodomain and a functional yet dubiously druggable ATPase domain. A small-molecule inhibitor approach to SMARCA biology seemed unlikely. The Ciulli laboratory has now solved the ‘SMARCA function inhibition dilemma’ using a PROTAC strategy6.

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Fig. 1: SMARCA2 presents two domains: the druggable bromodomain and the functional ATPase domain.

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  1. Discovery Network Group, Pfizer Medicine Design, Cambridge, MA, USA

    Dafydd Owen

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Correspondence to Dafydd Owen.

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Dafydd Owen is a shareholder in Pfizer Inc.

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Owen, D. Choosing your druggability battle. Nat Chem Biol 15, 652–653 (2019). https://doi.org/10.1038/s41589-019-0305-7

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