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FGFR allosteric inhibition

Sanofi and collaborators at the Flanders Institute for Biotechnology at Catholic University Leuven have serendipitously discovered an allosteric inhibitor of the cancer target fibroblast growth factor receptor. The team hopes the allosteric mechanism will lead to improved safety over molecules that bind the receptor's active site and that the identification of this molecule will pave the way for designing other allosteric inhibitors-a process that has proven challenging.1,2

Fibroblast growth factor receptor (FGFR) is often mutated and overexpressed in cancers, in which it plays a role in angiogenesis. The FGFR family is made up of 4 different receptors, all of which have different splice variants, and 22 different ligands.

Although some FGFR signaling pathways contribute to cancer pathogenesis, others are important for normal physiological functioning. Nonspecific inhibition of FGFR signaling can cause serious side effects such as hyperphosphatemia.

Thus, inhibiting the target can cause both on- and off-target toxicities. In addition, FGFR inhibitors often have cross-reactivity with other receptor tyrosine kinases, which can lead to problems with blood

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