Zoligratinib (Debio-1347)

Catalog No.S7665 Batch:S766503

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Technical Data

Formula

C20H16N6O
Molecular Weight 356.38 CAS No. 1265229-25-1
Solubility (25°C)* In vitro DMSO 71 mg/mL (199.22 mM)
Ethanol 3 mg/mL (8.41 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Zoligratinib (Debio-1347, CH5183284, FF284) is a selective and orally available FGFR inhibitor with IC50 of 9.3 nM, 7.6 nM, 22 nM, and 290 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively. Phase 1.
Targets
FGFR2 [1]
(Cell-free assay)		 FGFR1 [1]
(Cell-free assay)		 FGFR3 [1]
(Cell-free assay)		 FGFR4 [1]
(Cell-free assay)
7.6 nM 9.3 nM 22 nM 290 nM
In vitro In cell-based assay, CH5183284 prevents autophosphorylation of FGFR1, FGFR2, and FGFR3 at 100 to 300 nM in the DMS114 (FGFR1 amplification), SNU-16 (FGFR2 amplification), and KMS11 [t(4;14) translocation and FGFR3 Y373C mutation] cell lines. CH5183284 thus produces selective antiproliferative activity against cancer cell lines harboring genetic alterations in FGFR. CH5183284 also inhibit FGFR2 harboring one type of the gatekeeper mutation (V564F) that causes resistance to other FGFR inhibitors. [1]
In vivo CH5183284 (100 mg/kg/day, p.o.) shows selective and significant antitumor activity against xenografts with FGFR genetic alterations such as KG1 (leukemia, FGFR1OP-FGFR1 fusion), SNU-16 (gastric cancer, FGFR2 amplification), MFE-280 (endometrial cancer, FGFR2 S252W mutation), UM-UC-14 (bladder cancer, FGFR3 S249C mutation), and RT112/84 (bladder cancer, FGFR3-TACC3 fusion). [1]

Protocol (from reference)

Kinase Assay:[1]
  • Protein kinase assay

    The inhibitory activity of CH5183284/Debio 1347 against FGFR1 is evaluated using a radiometric filter assay by measuring the incorporation of 33Pi with a microplate scintillation counter. The phosphorylation activities of LCK, EGFR, KIT, MET, SRC, BRK, FGFR2, Flt3, LTK, INSR, YES, ABL, EPHA2, ZAP70, Fyn, IGF1R, KDR, and PDGFR on substrate peptides are determined by homogeneous time-resolved fluorescence assay with LANCE Eu-W1024 labeled anti-phosphotyrosine PT66 antibody according to standard methods. Time-resolved fluorescence is measured with an EnVision HTS microplate reader. The activities of Aurora A, Akt1/PKBα, PKA, Cdk1/cyclin B, Cdk2/cyclin A, PKCα, PKCβ1 and PKCβ2 on substrate peptides are determined by IMAP FP Screening Express Progressive Binding System. Fluorescence polarization is measured with an EnVision HTS microplate reader.
Cell Assay:[1]
  • Cell lines

    327 human tumor cell lines

  • Concentrations

    ~10 μM

  • Incubation Time

    4 days

  • Method

    The cell lines are added to the wells of 96-well plates containing 0.076 to 10,000 nM CH5183284/Debio 1347 and incubated at 37°C. After 4 days of incubation, Cell Counting Kit-8 solution is added and, after incubation for several more hours, absorbance at 450 nm is measured with the iMark Microplate-Reader. The antiproliferative activity is calculated using the formula (1 − T/C) × 100 (%), where T and C represent absorbance at 450 nm of the cells treated with drugs (T) and that of untreated control cells (C). The IC50 values are calculated using Microsoft Excel 2007.
Animal Study:[1]
  • Animal Models

    Mice bearing KG1, SNU-16, MFE280, UM-UC-14, RT112/84, or MKN-45 tumors

  • Dosages

    100 mg/kg/day

  • Administration

    p.o.

Selleck's Zoligratinib (Debio-1347) has been cited by 12 publications

Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer [ Cancer Discov, 2023, 13(9):1998-2011] PubMed: 37377403
Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer [ Cancer Discov, 2023, 13(9):1998-2011] PubMed: 37377403
Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer [ Cancer Discov, 2023, 13(9):1998-2011] PubMed: 37377403
Modeling unveils sex differences of signaling networks in mouse embryonic stem cells [ Mol Syst Biol, 2023, e11510.] PubMed: 37735975
Novel involvement of PLD-PKCδ-CREB axis in regulating FGF-2-mediated pentraxin 3 production in human nasal fibroblast cells [ J Cell Physiol, 2021, 10.1002/jcp.30657] PubMed: 34897684
Cross-talk between LAM cells and fibroblasts may influence alveolar epithelial cell behavior in Lymphangioleiomyomatosis [ Am J Physiol Lung Cell Mol Physiol, 2021, 10.1152/ajplung.00351.2021] PubMed: 34936509
Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer. [ Clin Cancer Res, 2019, 10.1158/1078-0432.CCR-19-1104] PubMed: 31585938
N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration. [ Elife, 2019, 8] PubMed: 31577229
Retinoic acid signaling balances adult distal lung epithelial progenitor cell growth and differentiation [Ng-Blichfeldt JP, et al. EBioMedicine, 2018, 36:461-474] PubMed: 30236449
A Three-Dimensional Organoid Culture Model to Assess the Influence of Chemicals on Morphogenetic Fusion. [ Toxicol Sci, 2018, 166(2):394-408] PubMed: 30496568

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