Rogaratinib

• CAT Number: I009176
• CAS Number: 1443530-05-9
• Molecular Formula: C23H26N6O3S
• Molecular Weight: 466.56
• Purity: ≥95%
• Synonyms: Rogaratinib; BAY-1163877: BAY1163877: BAY 1163877;4-((4-amino-5-(7-methoxy-5-methylbenzo[b]thiophen-2-yl)-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl)piperazin-2-one
• Target: FGFR
• Solubility: Soluble in DMSO
• Storage: Desiccate at RT
• IUPAC Name: 4-[[4-amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl]piperazin-2-one
• InChI: InChI=1S/C23H26N6O3S/c1-13-6-14-8-18(33-22(14)17(7-13)32-3)20-15(11-31-2)16(9-28-5-4-25-19(30)10-28)29-21(20)23(24)26-12-27-29/h6-8,12H,4-5,9-11H2,1-3H3,(H,25,30)(H2,24,26,27)
• InChIKey: HNLRRJSKGXOYNO-UHFFFAOYSA-N
• SMILES: CC1=CC2=C(C(=C1)OC)SC(=C2)C3=C4C(=NC=NN4C(=C3COC)CN5CCNC(=O)C5)N

Rogaratinib (Cat No.:I009176) is a potent and selective tyrosine kinase inhibitor with potential antineoplastic activity. It primarily targets the fibroblast growth factor receptor (FGFR) family, inhibiting their activation and downstream signaling pathways involved in cell proliferation, angiogenesis, and tumor growth. Rogaratinib’s unique binding mode allows it to overcome certain resistance mutations commonly associated with FGFR inhibitors. This chemical has shown promise in preclinical and clinical studies for the treatment of advanced solid tumors, including FGFR-altered cancers, making it a potential candidate for targeted therapy in oncology.

Reference

1. Oncogenesis. 2016 Jul 18;5(7):e241. doi: 10.1038/oncsis.2016.48.
Activation of the Met kinase confers acquired drug resistance in FGFR-targeted
lung cancer therapy.
Kim SM(1), Kim H(1), Yun MR(1), Kang HN(1), Pyo KH(1), Park HJ(1), Lee JM(1),
Choi HM(1), Ellinghaus P(2), Ocker M(2), Paik S(3)(4), Kim HR(5), Cho BC(5).
Author information:
(1)JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi, Kyungbuk, Korea.
(2)Bayer Pharma AG, Global Drug Discovery, Wuppertal, Germany.
(3)Division of Pathology NSABP, Pittsburgh, PA, USA.
(4)Severance Biomedical Science Institute, Yonsei University College of Medicine,
Seoul, Korea.
(5)Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer
Center, Yonsei University College of Medicine, Seoul, Korea.
Aberrant fibroblast growth factor receptor (FGFR) activation/expression is a
common feature in lung cancer (LC). In this study, we evaluated the antitumor
activity of and the mechanisms underlying acquired resistance to two potent
selective FGFR inhibitors, AZD4547 and BAY116387, in LC cell lines. The antitumor
activity of AZD4547 and BAY1163877 was screened in 24 LC cell lines, including 5
with FGFR1 amplification. Two cell lines containing FGFR1 amplifications, H1581
and DMS114, were sensitive to FGFR inhibitors (IC50<250 nm). Clones of
FGFR1-amplified H1581 cells resistant to AZD4547 or BAY116387 (H1581AR and
H1581BR cells, respectively) were established. Receptor tyrosine kinase (RTK)
array and immunoblotting analyses showed strong overexpression and activation of
Met in H1581AR/BR cells, compared with that in the parental cells. Gene set
enrichment analysis against the Kyoto Encyclopedia of Genes and Genomes (KEGG)
database showed that cytokine-cytokine receptor interaction pathways were
significantly enriched in H1581AR/BR cells, with Met contributing significantly
to the core enrichment. Genomic DNA quantitative PCR and fluorescent in situ
hybridization analyses showed MET amplification in H1581AR, but not in H1581BR,
cells. Met amplification drives acquired resistance to AZD4547 in H1581AR cells
by activating ErbB3. Combination treatment with FGFR inhibitors and an anaplastic
lymphoma kinase (ALK)/Met inhibitor, crizotinib, or Met-specific short
interfering RNA (siRNA) synergistically inhibited cell proliferation in both
H1581AR and H1581BR cells. Conversely, ectopic expression of Met in H1581 cells
conferred resistance to AZD4547 and BAY1163877. Acquired resistance to FGFR
inhibitors not only altered cellular morphology, but also promoted migration and
invasion of resistant clones, in part by inducing epithelial-to-mesenchymal
transition. Taken together, our data suggest that Met activation is sufficient to
bypass dependency on FGFR signaling. Concurrent inhibition of the Met and FGFR
pathways may have synergistic clinical benefits when targeting FGFR-dependent LC.