Pemigatinib binds to the inactive conformation
of FGFR1 with the activation loop adopting a DFG-in
conformation (type I1/2 inhibitor). The
pyrrolopyridine moiety forms two hydrogen bonds
with the NH and the carbonyl of Ala564 in the hinge
region (Figs. 3, 4). The difluoromethoxyphenyl ring,
which is perpendicular relative to the tricyclic ring, fits
the specificity pocket containing the gatekeeper
residue Val561. One of the methoxy oxygen atoms
hydrogen bonds to the backbone NH of Asp641. The
terminal morpholine extends towards the solventfront region, and makes only minor contacts with the
protein.
Pemigatinib is a potent inhibitor of FGFRs for the treatment of cholangiocarcinoma.
Pemigatinib is indicated for the treatment of previously treated adult patients with unresectable locally advanced or metastatic cholangiocarcinoma (CCA) who have been identified by an FDA-approved test for the presence of fibroblast growth factor receptor 2 (FGFR2) fusions or other rearrangements.
Class: receptor tyrosine kinase;
Treatment: metastatic cholangiocarcinoma;
Other name: INCB054828;
Elimination half-life = 15 h;
Protein binding = 90.6%
Removal of the acetaldehyde protecting group in compound 284 under acidic conditions afforded aldehyde 285. Reductive amination of aldehyde 285 with aniline 286 gave benzylamine 287. Benzylamine 287 reacted with isocyanate 288 to form the desired urea 289. In the presence of a strong base, LHMDS (lithium dimethylsilane), compound 289 underwent intramolecular cyclization to displace the adjacent chlorine atom to yield azatricyclic compound 290. Conventional hydrolysis to remove the benzenesulfonyl group completed the construction of pemitinib, affording the final product in good yield.
Primary targets: Pan-FGFR
FGFR1/2/3/4 IC 50 = 0.4, 0.5, 1, 30 nM
