The story of erdafitinib – abridged

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.