In April we celebrated the FDA
approval of erdafitinib for certain types of urothelial carcinomas with genetic
alterations in the FGFR2 or FGFR3 genes. This marked the third launch of a fragment-derived
drug. However, although erdafitinib was mentioned in a 2016 review, the
fragment origins have remained obscure. The full story has yet to be published,
but Chris Murray (Astex), David Newell (Newcastle University) and Patrick
Angibuad (Janssen) have recently published brief highlights in MedChemComm.
The story begins all the way back
in 2006, with a collaboration between Astex and the Northern Institute of
Cancer Research at Newcastle University. The four fibroblast growth factor
receptors (FGFR1-4) are kinases whose aberrant activation was known to be
associated with multiple cancers. In those days most FGFR inhibitors also
inhibited VEGFR2, which was linked to unacceptable side effects. A fragment screen
in 2008 led to a series of potent, selective molecules and enticed Janssen to
join the collaboration. This particular lead series was ultimately discontinued,
though, as discussed below, it turned out to be important.
Meanwhile, fragment 1 was
identified, characterized crystallographically bound to FGFR1, and improved to
low micromolar compound 2. (Note: the structure of Fragment 1 has been corrected.) Virtual screening and medicinal chemistry led to
compound 4, with improved selectivity for FGFR3 over VEGFR2. Superimposing the
crystal structure of this compound with the previous series suggested building
off the aniline nitrogen to improve potency (and, one might assume, solubility).
This ultimately led to erdafitinib.
The researchers highlight the cooperative
nature of this project. “Each team brought their specific expertise and most importantly,
wisely and collaboratively capitalized on each other’s strengths.”
The publication also illustrates that
success can take time – thirteen years in this case. This is not unusual for
drug discovery, and is in fact halfway between the remarkably fast six years
for vemurafenib, the first fragment-based drug approved, and the two decades
required for venetoclax, the second.
But in the end good things are
worth waiting for, and the 15-20% of metastatic bladder cancer patients with an
FGFR alteration now have a new treatment option. Erdafitinib is being tested in
at least a dozen other clinical trials for various cancers. Practical Fragments
wishes all the participants the best of luck.
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