Name: Lirafugratinib (Lyrfigtu) in Previously treated FGFR2 fusion or rearrangement-positive cholangiocarcinoma: Mechanism of action
Published: 2026-09-27T09:44:05-04:00

Product information and disease description Product description Product information Pharmacology

Mechanism of action

5 evidence topics · 4 sources

Mechanism of action in the prescribing information

“Lirafugratinib is a small molecule kinase inhibitor that inhibits FGFR2. Lirafugratinib covalently binds FGFR2. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Lirafugratinib inhibited FGFR2 phosphorylation and downstream signaling and decreased cell viability in cancer cell lines with FGFR2 alterations, including FGFR fusions/rearrangements, amplifications, and mutations.” (opens the prescribing information at this quote)

Covalent binding to FGFR2 Cys491 and the basis of isoform selectivity

“We leveraged differences in conformational dynamics between FGFR2 and other FGFRs observed through long timescale molecular dynamics simulations to enable the design of RLY-4008, an FGFR2-selective inhibitor that covalently binds to Cys491 (Fig. 1B).” (opens the source at this quote in a new tab)
“Although FGFR2 was labeled rapidly (t1/2 = 8 s), labeling of FGFR1 occurred much more slowly (t1/2 = 351 s; Fig. 1D), consistent with the observation from molecular dynamics simulations that RLY-4008 induces a conformation in FGFR1 that is not favorable for covalent bond formation.” (opens the source at this quote in a new tab)
“In contrast, the irreversible pan-FGFRi, futibatinib, covalently labeled both FGFR1 and FGFR2 at a similar rate (FGFR1 t1/2 = 8 s; FGFR2 t1/2 = 13 s) under identical experimental conditions (Fig. 1E), consistent with its reported covalent inhibition of all FGFRs” (opens the source at this quote in a new tab)

“Simulations of FGFR1 binding one of our early selective compounds suggested that its selectivity arose because the compound stabilized the FGFR1 P-loop in an extended conformation with such a low degree of flexibility that covalent engagement of Cys488 (homologous to FGFR2 Cys491) was discouraged.” (opens the source at this quote in a new tab)

Selectivity over FGFR1, FGFR3, and FGFR4

“RLY-4008 demonstrates potent inhibition of FGFR2 enzyme activity in biochemical assays (IC50 = 3 nmol/L) but markedly weaker inhibition of other FGFRs (Supplementary Table S2). RLY-4008 has >250-fold selectivity over FGFR1, and >80- and >5,000-fold selectivity over FGFR3 and FGFR4, respectively (Fig. 1G).” (opens the source at this quote in a new tab)
“Therefore, FGFR2 is the only kinase expected to be irreversibly inhibited by RLY-4008, resulting in previously unachieved selectivity.” (opens the source at this quote in a new tab)

“Lirafugratinib demonstrated the highest selectivity to inhibit FGFR2 without substantial inhibition of FGFR1, 3, 4 compared to the other FGFR inhibitors tested.” (opens the source at this quote in a new tab)

Rationale for sparing FGFR1 and FGFR4: hyperphosphatemia and diarrhea

“Hyperphosphatemia is attributed to the inhibition of FGFR1, which then increases phosphate reabsorption in the kidney” (opens the source at this quote in a new tab)
“In addition, diarrhea is reported in 15% to 36% of patients (all CTCAE grades), owing to inhibition of FGFR4” (opens the source at this quote in a new tab)

“Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.” (opens the source at this quote in a new tab)

Activity against FGFR2 resistance mutations, including the V564F gatekeeper mutation

“Our data align with these clinical findings, showing that current pan-FGFRi do not retain potency on FGFR2V564F, resulting in a >55-fold shift in IC50 between FGFR2WT and this mutation. In contrast, RLY-4008 is more potent on FGFR2V564F than FGFR2WT.” (opens the source at this quote in a new tab)
“For the FGFR2N549K mutation, RLY-4008 and futibatinib demonstrate an ∼10-fold shift in potency relative to FGFR2WT, whereas other pan-FGFRi demonstrate shifts of ∼30 to >100-fold.” (opens the source at this quote in a new tab)