Rapidly proliferating cancer cells
require a steady supply of nucleic acids, and cutting that off is a potential
therapy. The enzyme dihydroorotate dehydrogenase (DHODH), which is important for
pyrimidine synthesis, is thus an interesting drug target. In a recent ACS
Med. Chem. Lett. paper, Lindsey DeRatt, Scott Kuduk, and colleagues at
Janssen describe their approach.
The researchers had previously
used virtual screening and structure-based drug design to develop compound 1,
which is potent in both biochemical and cell-based assays. However, the
molecule is highly effluxed by P-glycoprotein, which can limit both oral bioavailability
and brain penetration. Thus, they turned to fragments.
An SPR screen (about which sadly
no details are provided) yielded compound 2, and crystallography revealed that
the amide carbonyl makes a similar contact to tyrosine 356 (Y356) as does the
carbonyl in the triazolone moiety of compound 1. Merging these led to compound
4, which was considerably more potent than compound 2 but much less so than compound
1. However, further optimization led eventually to compound 25. Although less
potent in an enzymatic assay than compound 1, compound 25 is equally effective
in cells. It also has excellent pharmacokinetics in mice and – importantly – a considerably
lower efflux ratio.
Interestingly, when the
researchers solved the crystal structure of a related molecule bound to DHODH,
they found that the carbonyl no longer interacts with Y356 but is instead
flipped 180ยบ and interacts with a different residue. The researchers conclude
by stating that they are designing new molecules to reengage Y356, which could
further improve potency.
Several lessons emerge from this
brief paper. First, the flipped urea moiety is another reminder that fragments do
not always maintain their orientations, as also seen here, here, and here. Second, information
from the fragment was used not to improve potency but rather to address other
aspects of an existing lead series, as seen here and here. And finally, one could
argue that the only critical feature of the fragment remaining in the final molecule
is the NH of the urea. But the fragment did cause the researchers to examine their molecules from a different perspective, resulting in a better series. Perhaps you could call this an example of fragment-assisted drug discovery. As is so
often the case, fragments can inspire new ideas that may otherwise be
overlooked.
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