Futibatinib is a medication that in September 2022 received accelerated approval by the FDA for the treatment of cholangiocarcinoma.
Disease: oncology
Target: FGFR - Tyrosine Kinase.
Mechanism of Action: Irreversible inhibitor.
Chemistry section: Retrosynthesis & Forward Synthesis.
Alterations of fibroblast growth factor receptors (FGFR) have been identified to be important for progression and development of several types of cancer, including cholangiocarcinoma. In this setting, inhibition of FGF receptor signaling is a promising therapeutic strategy for cancer treatment. One modality of FGF receptor inhibitor is the use of small molecule compounds that bind to the ATP-binding site of the receptor at the tyrosine kinase domain and successfully block cross-phosphorylation and subsequent cell signaling.
Futibatinib presents an ATP-mimicking pyrazolopyrimidine core structure in the middle, a pyrrolidine moiety overlapping with the sugar part of ATP, an acrylamide functional group at the edge, and a straight-chain alkyne to add the necessary chemical space for a dimethoxyphenyl ring to bind into a hydrophobic pocket of the receptor.
Sources and references:
Futibatinib:
1. ACS Med. Chem. Lett. 2023, 14, 4, 396-404. doi.org/10.102...
2. ChemMedChem 2019, 14, 494. doi.org/10.100...
FGFR:
1. Nat Rev Cancer 10, 116-129 (2010). doi.org/10.103...
Covalent Inhibitors and Warheads:
1. J. Med. Chem. 2022, 65, 1, 58-83. doi.org/10.102...
2. Current Opinion in Chemical Biology 2017, 39:54-63. doi.org/10.101...
3. J. Med. Chem. 2019, 62, 12, 5673-5724. doi.org/10.102...
Futibatinib-FGFR 1 Covalent Complex: PDB ID: 6MZW.
23 сен 2024
