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Regorafenib: a new multifunctional kinase inhibitor approved by FDA

Tags kinase inhibitors polypharmacology metastatic colorectal cancer
By: Rafael Najmanovich  
September 27 2012

A new multifunctional inhibitor against VEGFR-2 (a.k.a KDR) and TIE2 kinases developed by Bayer and Onyx has been approved by the FDA to treat metastatic colorectal cancer. This represents a step forward in polypharmacology where I always encounter the same argument against it: "Why not 'simply' develop two inhibitors"? (single quotes placed by me). Answer: as it it wasn't hard enough to create one, two is, well, twice as hard. There are other minor arguments about the treatment being easier for the patient to follow. Anyway, the the structure of the kinase domains of the two kinases involved are known and I shall try to dock the drug later to see how it may bind to both proteins. Interestingly, both proteins have been tested by Davis [1], and so have been their two closest neighbours in the kinome tree (see attached figure produced using our kinome render tool). I wonder how specific is Regorafenib... As a matter of fact, not that specific at all [2]. In fact, it seems to be as much a shotgun as most other (kinase) inhibitors.

1. Davis, M. I. et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol 29, 1046–1051 (2011).

2. Wilhelm, S. M. et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 129, 245–255 (2011).

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