WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H561861
CAS#: 1513857-77-6 (free base)
Description: Pemigatinib, also known as INCB054828, is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3), with potential antineoplastic activity. FGFR inhibitor INCB054828 binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-related signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells.
Hodoodo Cat#: H561861
Name: Pemigatinib
CAS#: 1513857-77-6 (free base)
Chemical Formula: C24H27F2N5O4
Exact Mass: 487.20
Molecular Weight: 487.500
Elemental Analysis: C, 59.13; H, 5.58; F, 7.79; N, 14.37; O, 13.13
Related CAS #: 1513857-77-6 (free base) 1513857-77-6 (HCl)
Synonym: Pemigatinib; INCB054828; INCB-054828; INCB 054828; INCB54828; INCB 54828; INCB-54828
IUPAC/Chemical Name: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-[(morpholin-4-yl)methyl]-1,3,4,7-tetrahydro-2Hpyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one
InChi Key: HCDMJFOHIXMBOV-UHFFFAOYSA-N
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)
SMILES Code: O=C1N(CC)C2=C3C(NC(CN4CCOCC4)=C3)=NC=C2CN1C5=C(F)C(OC)=CC(OC)=C5F
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | Pemigatinib (INCB054828) is an orally active, selective FGFR inhibitor with IC50s of 0.4 nM, 0.5 nM, 1.2 nM, 30 nM for FGFR1, FGFR2, FGFR3, FGFR4, respectively. |
| In vitro activity: | To investigate the effect of INCB054828 treatment on intracellular signaling, Western blot analysis was used for markers of FGFR pathway activation. 2 cell lines were chosen that were derived from malignancies associated with genetically activated FGFR1 (KG1a, 8p11-positive acute myeloid leukemia [AML]) and FGFR3 (RT-4, urothelial carcinoma) that are also indications in which INCB054828 is currently being investigated in phase 2 clinical trials. In the KG1a cell line that bears an FGFR1OP2-FGFR1 translocation, a concentration of greater than 5 nM reduced levels of phospho-FGFR to basal levels (Fig 2A). Phospho-ERK and phospho-STAT5 are also reduced with the same concentration dependence, consistent with potent suppression of FGFR activation by the inhibitor. Treatment of the bladder cancer line RT-4 that harbors an FGFR3-TACC3 translocation with INCB054828 strongly suppresses levels of phospho-FRS2, a scaffolding protein that is a substrate of FGFR, and phospho-ERK (Fig 2B). FGFR3 phosphorylation was not detectable by Western blotting; however, a decrease was detected by proximity ligation assay that uses polymerase chain reaction to amplify the signal from the bound antibodies to phospho- and total FGFR3 (S4 Fig). Using this method, potent inhibition of FGFR3 by INCB054828 (<10 nM) was confirmed in a second urothelial cell line RT-112 that also harbors the FGFR3-TACC3 fusion (Fig 2C). INCB054828 selectively inhibits the growth of tumor cell lines with activation of FGFR signaling (Table 1). The most sensitive lines had GI50 values (concentration required to inhibit growth by 50%) less than 15 nM. In comparison, the GI50 values for a panel of hematologic and solid tumor cell lines that lacked known alterations in the FGFR genes exceeded 2,500 nM (S3 Table); many of these cell lines are known to have dependencies on other oncogenes (e.g. EGFR, HCC-422; K-Ras, A549, and UMUC3). The data reveal a clear separation in sensitivity to INCB054828 between cell lines with genetic alterations in FGFR1, FGFR2, or FGFR3 and cell lines lacking these aberrations. Furthermore, there was no inhibition of the proliferation of primary T cells from normal donors up to 1,500 nM (S5 Fig). Reference: PLoS One. 2020 Apr 21;15(4):e0231877. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32315352/ |
| In vivo activity: | The antitumor effect of orally dosed INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1 (KG1), FGFR2 (KATO III), and FGFR3 (RT-112). A full dose-response was evaluated using the KATO III gastric cancer model harboring genetic amplification of FGFR2 (Fig 4A). A once-daily dose of 0.03 mg/kg INCB054828 significantly suppressed tumor growth while maximum activity was observed at doses equal to or greater than 0.3 mg/kg once daily. The KG1 erythroleukemia AML cell line carries a translocation of FGFR1 (FGFROP2-FGFR1) that has been described in patients with 8p11 myeloproliferative neoplasms. It is the parental line to KG1a, and the in vitro activity of INCB054828 against KG1 and KG1a is similar (GI50 values 1 and 3 nM, respectively). A once-daily dose of 0.3 mg/kg showed significant efficacy (P < 0.05; Fig 4B) against the KG1 subcutaneous xenograft in a humanized mouse NSG mice engrafted with human CD34+ umbilical cord blood cells. Finally, the activity of INCB054828 was evaluated against an FGFR3-dependent model, RT-112 bladder carcinoma that carries the FGFR3-TACC3 fusion. This xenograft model was established subcutaneously into nude rats, and oral administration of 0.3 and 1 mg/kg INCB054828 resulted in significant tumor growth inhibition (Fig 4C). Collectively, these data confirm the balanced activity of INCB054828 against FGFR1, 2, and 3 and show that significant efficacy can be achieved with low daily doses. Plasma levels of INCB054828 showed less than 2-fold variation among the xenograft studies at the 1-mg/kg dose for mouse studies. Reference: PLoS One. 2020 Apr 21;15(4):e0231877. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32315352/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 40.0 | 82.05 |
The following data is based on the product molecular weight 487.50 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | |
| In vitro protocol: | 1. Liu PCC, Koblish H, Wu L, Bowman K, Diamond S, DiMatteo D, Zhang Y, Hansbury M, Rupar M, Wen X, Collier P, Feldman P, Klabe R, Burke KA, Soloviev M, Gardiner C, He X, Volgina A, Covington M, Ruggeri B, Wynn R, Burn TC, Scherle P, Yeleswaram S, Yao W, Huber R, Hollis G. INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models. PLoS One. 2020 Apr 21;15(4):e0231877. doi: 10.1371/journal.pone.0231877. PMID: 32315352; PMCID: PMC7313537. |
| In vivo protocol: | 1. Liu PCC, Koblish H, Wu L, Bowman K, Diamond S, DiMatteo D, Zhang Y, Hansbury M, Rupar M, Wen X, Collier P, Feldman P, Klabe R, Burke KA, Soloviev M, Gardiner C, He X, Volgina A, Covington M, Ruggeri B, Wynn R, Burn TC, Scherle P, Yeleswaram S, Yao W, Huber R, Hollis G. INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models. PLoS One. 2020 Apr 21;15(4):e0231877. doi: 10.1371/journal.pone.0231877. PMID: 32315352; PMCID: PMC7313537. |
