31 July 2017

Fragments in the clinic: PF-06650833

Of the more than 30 fragment-derived drugs that have entered clinical development, more than a third target kinases. While most of these are being developed against various types of cancer, a new paper in J. Med. Chem. by Katherine Lee, Stephen Wright, and their Pfizer colleagues describes the discovery of a compound that inhibits interleukin-1 receptor associated kinase 4 (IRAK4), a target for chronic autoimmune diseases. (Katherine also spoke about this project at FBLD 2016.) This details the earliest screens through development of the active clinical candidate.

The researchers started by screening their 2592-member Global Fragment Initiative library at 236 µM using STD NMR, resulting in 169 hits. A biochemical screen of the same library at 909 µM produced 160 hits, with 95 in common. Further triage using another assay along with modeling prioritized 15 fragments, of which 10 produced structures in co-crystallization trials. Fragment 51 was particularly interesting due to its impressive ligand efficiency and unusual binding mode to the hinge region of the kinase.

The crystal structure suggested that fragment growing could be productive, and indeed simply expanding the phenyl ring to a naphthyl improved the affinity to low micromolar for compound 10. Adding a nitrogen into the ring to lower lipophilicity while also adding a substituent to pick up additional interactions improved the affinity another order of magnitude (compound 14).


Guided by a co-crystal structure of compound 14 bound to IRAK4, the researchers used parallel chemistry to further improve the molecule, resulting in compound 20, which crystallography confirmed makes multiple interactions with the protein. Compound 20 also had promising selectivity and pharmacokinetic properties, but despite low nanomolar activity in a biochemical assay it had only high nanomolar potency in human peripheral blood mononuclear cells (PBMC).

At this point the medicinal chemistry began in earnest, again guided by structure and with a keen eye on maintaining good physicochemical properties. To a non-chemist the changes between compound 20 and PF-06650833 may appear subtle, but chemists will appreciate that you don’t introduce two new stereocenters without darn good reasons, which are discussed in depth in the paper. The results paid off, with the final molecule showing low nanomolar potency in the PBMC assay, excellent selectivity against a broad panel of kinases and other targets, and attractive ADME properties. It was also orally active in an acute rat inflammation model.

Sometimes publications only appear after a compound has dropped out of development, but that is not the case here. Indeed, after completing four phase 1 studies, PF-06650833 is currently being tested in a phase 2 trial for rheumatoid arthritis. Watch this space!

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