28 August 2017

Fragments vs BET Bromodomains: FORMA’s story

Five years ago Teddy highlighted a paper from GlaxoSmithKline that reported the discovery and characterization of several different fragments that bind to members of the BET family of bromodomains, epigenetic readers that recognize acetylated lysine residues in histones. Researchers at FORMA were among those paying attention to these developments. David Millan and his colleagues have now published in ACS Med. Chem. Lett. their account of how they were able to advance one of these fragments to a chemical probe.

As the researchers note, many different BET inhibitors have been reported; we discussed two separate series just a few months ago. Chemical novelty was thus a challenge, particularly as they were starting with a fragment (compound 1) reported by a large company. They thus chose to tweak the fragment slightly to intermediate 2. Importantly, introduction of the second nitrogen also introduces another synthetic vector with potential to pick up interactions with the so-called “WPF shelf”. This explicit consideration of synthetic tractability in fragment design enables rapid progress.

Parallel chemistry led to compound 6, with measurable biochemical activity against BRD4. Further growing from the phenyl ring led to compound 8, with sub-micromolar biochemical and antiproliferative activity. A crystal structure revealed that the newly introduced amide functionality was pointed toward solvent, which would allow modulation of the physicochemical properties.

More medicinal chemistry followed, with considerable effort on improving the plasma and liver microsome stability. This campaign involved a combination of rational design and parallel synthesis along with a keen focus on minimizing lipophilicity. Ultimately the researchers arrived at FT001, with good activity and stability. This compound was also selective for BET family members over other bromodomains and displayed reasonable pharmacokinetics and impressive activity in a mouse xenograft model.

Last week we highlighted a paper that also started from a previously disclosed fragment to generate novel chemical matter. This paper provides another example of how useful public fragments can be in the hands of creative scientists.

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