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Pemigatinib (formerly INCB054828; INCB-054828; Pemazyre) is a novel, potent, orally bioavailable and selective FGFR inhibitor with IC50 of 0.4 nM, 0.5 nM, 1.2 nM, 30 nM for FGFR1, FGFR2, FGFR3, FGFR4, respectively. For the treatment of bile duct cancer (cholangiocarcinoma), pemigatinib has been approved as a medicine. Inhibiting FGFR1/2/3 through binding to it, INCB054828 may lead to the suppression of signal transduction pathways associated with FGFR1/2/3. When FGFR1/2/3 is overexpressed in tumor cells, this prevents their proliferation.
| Targets |
FGFR1 (IC50 = 0.4 nM); FGFR2 (IC50 = 0.5 nM); FGFR3 (IC50 = 1.2 nM); FGFR4 (IC50 = 30 nM)
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| ln Vitro |
Pemigatinib effectively reduces reactive astrocytes' ability to attract myeloid cells. Pemigatinib's potential to modulate FGFR may hold promise for promoting protective mechanisms in both human and murine systems and suppressing proinflammatory astrocyte responses.[2]
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| ln Vivo |
Pemigatinib does not appear to have any effect on the acute EAE disease course.[2]
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| Cell Assay |
Afatinib (10 μM), UNC2025 (10 μM), or pemigatinib (10 μM) were used for a 24-hour period to stimulate primary mouse astrocytes. ACM or a control medium was used to stimulate N2A neuronal cells for a full day. After being detached, primary mouse astrocytes and N2A neuronal cells were once again washed in cold 1× PBS. It was done using live/dead staining. Furthermore, annexin V–propidium iodide staining was carried out. Prior to being acquired on a 3L Cytek Northern Lights flow cytometer, cells were first rinsed and then resuspended in annexin V binding buffer. The OMIQ platform was used to analyze the flow cytometry data.
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| Animal Protocol |
Female C57Bl/6J mice of experimental autoimmune encephalomyelitis (EAE) model
2.5 mg/kg i.n. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following a single oral dose of 13.5 mg pemigatinib, the median time to peak concentration (Tmax) was 1.13 hours (0.50–6.00). With repeated once-daily dosing, steady-state concentrations were reached within 4 days, with a median drug accumulation ratio of 1.63 (range 0.63–3.28). Steady-state concentrations of pemigatinib increased dose-proportionately over a dose range of 1–20 mg (approximately 0.07–1.5 times the recommended dose). The mean steady-state AUC and Cmax were 2620 nM·h (coefficient of variation 54%) and 236 nM, respectively. Following a single oral dose of 11 mg of radiolabeled pemigatinib, approximately 82.4% of the dose was recovered in feces. Of the recovered drug, approximately 1.4% was unmetabolized parent compound. Approximately 12.6% of the dose was recovered in the urine, of which 1% was unmetabolized parent compound. Following a single oral dose of 13.5 mg pemigatinib, the apparent volume of distribution was 235 L (coefficient of variation 60.8%). Following a single oral dose of 13.5 mg pemigatinib, the geometric mean apparent clearance (CL/F) was 10.6 L/h (coefficient of variation 54%). Metabolites/Metabolites: In vitro studies have shown that pemigatinib is primarily metabolized by the CYP3A4 enzyme. Its specific metabolic pathway and metabolites have not been characterized. Biological Half-Life: Following a single oral dose of 13.5 mg pemigatinib, the geometric mean elimination half-life (t½) of pemigatinib was 15.4 (51.6% CV) hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In pre-registration clinical trials of pemigatinib, elevated ALT levels occurred in 43% to 50% of patients, with 4% to 12% experiencing ALT levels exceeding five times the upper limit of normal. Elevated serum bilirubin was also common, but typically occurred in patients with cholangiocarcinoma and partial or complete biliary obstruction. No clinically significant liver injury (with jaundice) or death due to liver failure caused by pemigatinib treatment was reported. These elevations were generally self-limiting and rapidly returned to normal regardless of dose adjustment. No clinically significant liver injury cases have been reported since pemigatinib's approval. However, overall clinical experience with this drug is limited, and the high incidence of elevated serum transaminases during treatment suggests the possibility of clinically significant liver injury. Probability Score: E (Unproven, but likely a rare cause of clinically significant liver injury). Effects during pregnancy and lactation ◉ Overview of use during lactation There is currently no information regarding the clinical use of pemigatinib during lactation. The manufacturer recommends discontinuing breastfeeding during treatment with pemigatinib and for one week after the last dose. ◉ Effects on breastfed infants As of the revision date, no relevant published information was found. ◉ Effects on lactation and breast milk As of the revision date, no relevant published information was found. Protein binding The in vitro serum protein binding rate of pemigatinib is 90.6%, with a drug concentration range of 1 to 10 µM. |
| References | |
| Additional Infomation |
Pharmacodynamics
Pemitinib is a small molecule kinase inhibitor that exerts its antitumor activity by inhibiting fibroblast growth factor receptor (FGFR). Pemitinib has an IC50 of less than 2 nM and exhibits potent inhibitory activity against FGFR1, FGFR2, and FGFR3. In mouse xenograft models of human tumors with altered FGFR1, FGFR2, or FGFR3, pemitinib demonstrates potent antitumor activity by inhibiting the growth of xenograft tumors. Furthermore, it has shown efficacy in patient-derived cholangiocarcinoma xenograft models expressing the oncogenic FGFR2 Transformer-2β homolog (TRA2b) fusion protein. Pemitinib also inhibits FGFR4 in vitro, but at concentrations approximately 100-fold higher than those inhibiting FGFR1, 2, and 3. |
| Molecular Formula |
C24H27F2N5O4
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|---|---|
| Molecular Weight |
487.4991
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| Exact Mass |
487.203
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| Elemental Analysis |
C, 59.13; H, 5.58; F, 7.79; N, 14.37; O, 13.13
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| CAS # |
1513857-77-6
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| Related CAS # |
1513857-77-6;1513857-77-6 (HCl);
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| PubChem CID |
86705695
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.620
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| LogP |
0.66
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
731
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C(=C([H])C(=C(C=1N1C(N(C([H])([H])C([H])([H])[H])C2C(=C([H])N=C3C=2C([H])=C(C([H])([H])N2C([H])([H])C([H])([H])OC([H])([H])C2([H])[H])N3[H])C1([H])[H])=O)F)OC([H])([H])[H])OC([H])([H])[H]
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| InChi Key |
HCDMJFOHIXMBOV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H27F2N5O4/c1-4-30-21-14(11-27-23-16(21)9-15(28-23)13-29-5-7-35-8-6-29)12-31(24(30)32)22-19(25)17(33-2)10-18(34-3)20(22)26/h9-11H,4-8,12-13H2,1-3H3,(H,27,28)
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| Chemical Name |
11-(2,6-difluoro-3,5-dimethoxyphenyl)-13-ethyl-4-(morpholin-4-ylmethyl)-5,7,11,13-tetrazatricyclo[7.4.0.02,6]trideca-1,3,6,8-tetraen-12-one
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| Synonyms |
INCB054828; INCB54828; INCB-054828; INCB 054828; INCB 54828; INCB-54828
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 25~40 mg/mL (51.3~82.1 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (5.64 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (4.27 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: (saturation unknown) in (add these co-solvents sequentially from left to right, and one by one), |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0513 mL | 10.2564 mL | 20.5128 mL | |
| 5 mM | 0.4103 mL | 2.0513 mL | 4.1026 mL | |
| 10 mM | 0.2051 mL | 1.0256 mL | 2.0513 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
The Purpose of the Study is to Continue to Provide Pemigatinib to Patients With Advanced Malignancies.
CTID: NCT04949191
Phase: Phase 2 Status: Terminated
Date: 2024-09-19
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Products are for research use only; We do not sell to patients
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