molecules of the month

FGF401 (roblitinib)

oral reversible-covalent FGFR4 kinase inhibitor

first sel. FGFR4i in clinical studies; for HCC

from biochemical HTS and SBDD

J. Med. Chem., Oct. 1, 2020

Novartis, Basel, CH

1 min read

FGF401 (roblitinib) is a highly selective, reversible-covalent inhibitor of the kinase FGFR4, a receptor that can drive progression of certain cancers. The Novartis team found that the FGFR4 protein has a high re-synthesis rate and therefore would require significant drug exposure to have a meaningful effect, so they deprioritized irreversible covalent starting points and pursued a potentially safer reversible-covalent strategy instead. The aldehyde of roblitinib targets a unique Cys by the hinge region of the protein (GK+2) that is not present in the other FGFR’s and is present in only 4 other kinases. It is remarkable that they were able to optimize an aldehyde for clinical oral dosing, and given the recent approval of another aldehyde drug, voxelotor, it is certain that aldehydes…

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