The epigenetic readers known as
bromodomains have been popular anticancer targets for fragment-based approaches. But rapid
success in generating potent molecules has not led to equally rapid success in
the clinic, in part due to toxicity. Many early molecules inhibited both of the
bromodomains (BD1 and BD2) present in the four BET family proteins, and some
evidence suggests that BD2-selective inhibitors would be better tolerated.
Indeed, last year we wrote about AbbVie’s selective clinical compound. Now
GlaxoSmithKline has just reported a new selective inhibitor in J. Med. Chem.
GlaxoSmithKline had previously discovered
the BD2-selective molecule GSK620, which unfortunately suffered from low
solubility in FaSSIF (fasted state simulated intestinal fluid). To try to improve
this molecule, they turned to fragments. Although the screening details are not
described here, the company’s first fragment screens against bromodomains from a decade ago provided dozens of crystallographically-characterized starting
points. Compound 6 binds in a similar manner to GSK620 and has good ligand efficiency.
Compound 6 shows equal potency
against BD1 and BD2 of BRD4, but merging the five-membered core with GSK620 led
to BD2-selective compound (S)-11. (Although compound 6 contains a pyrrole, the
NH was inconveniently positioned and thus the researchers explored other
five-membered heterocycles during scaffold hopping; the paper describes furan
and pyrazole series.) Further optimization of
the furan, in part based on earlier SAR, ultimately led to GSK743.
This molecule showed greater than
1000-fold selectivity for the BD2 bromodomain of BRD4 over the BD1 domain, and >300-fold
selectivity for the BD2 domains of BRD2, BRD3, and BRDT as well as selectivity against a
large panel of other bromodomains. More extensive profiling revealed it to be
clean against CYP3A4, hERG, and other potential off-targets, and it was also
negative in an Ames test for mutagenicity. Pharmacokinetics and oral bioavailability
were also reasonable in both rat and dog. The compound had potent antiproliferative activity against acute myeloid leukemia cell lines. Finally, FaSSIF solubility was at
least 20-fold better than for GSK620.
This is a nice example of
fragment-based scaffold hopping, akin to another example from GlaxoSmithKline
we highlighted last year. Whether GSK743 ultimately advances will probably
depend on how other molecules in the class perform. Biology will have the final
say, but fragments – combined with elegant medicinal chemistry – provided the
tools to answer the questions.
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