Abstract

In the present study, we examined the antitumor activity of a series of trichlorobenzene-substituted azaaryl compounds and identified MPT0L145 as a novel FGFR inhibitor with better selectivity for FGFR1, 2 and 3. It was preferentially effective in FGFR-activated cancer cells, including bladder cancer cell lines expressing FGFR3-TACC3 fusion proteins (RT-112, RT-4). MPT0L145 decreased the phosphorylation of FGFR1, FGFR3 and their downstream proteins (FRS2, ERK and Akt). Mechanistically, cDNA microarray analysis revealed that MPT0L145 decreased genes associated cell cycle progression, and increased genes associated with autophagy pathway. Accordingly, the data revealed that MPT0L145 induced G0/G1 cell cycle arrest and decreased protein levels of cyclin E. Moreover, we provided the evidence that autophagy contributes to FGFR inhibitor-related cell death. Finally, MPT0L145 exhibited comparable antitumor activity to cisplatin with better safety in a RT-112 xenograft model. Taken together, these findings support the utility of MPT0L145 as a novel FGFR inhibitor, providing a strong rationale for further evaluation of this compound as a therapeutic agent for bladder cancers.

Original languageEnglish
Pages (from-to)26374-26387
Number of pages14
JournalOncotarget
Volume7
Issue number18
DOIs
Publication statusPublished - May 1 2016

Fingerprint

Urinary Bladder Neoplasms
Autophagy
G1 Phase Cell Cycle Checkpoints
cdc Genes
Cyclin E
Proteins
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Heterografts
Cisplatin
Cell Death
Phosphorylation
Safety
Cell Line
Genes
In Vitro Techniques
trichlorobenzene
Neoplasms
Therapeutics

Keywords

  • Autophagy
  • Bladder cancer
  • Cell cycle
  • FGFR
  • FGFR3-TACC3

ASJC Scopus subject areas

  • Oncology

Cite this

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title = "Trichlorobenzene-substituted azaaryl compounds as novel FGFR inhibitors exhibiting potent antitumor activity in bladder cancer cells in vitro and in vivo",
abstract = "In the present study, we examined the antitumor activity of a series of trichlorobenzene-substituted azaaryl compounds and identified MPT0L145 as a novel FGFR inhibitor with better selectivity for FGFR1, 2 and 3. It was preferentially effective in FGFR-activated cancer cells, including bladder cancer cell lines expressing FGFR3-TACC3 fusion proteins (RT-112, RT-4). MPT0L145 decreased the phosphorylation of FGFR1, FGFR3 and their downstream proteins (FRS2, ERK and Akt). Mechanistically, cDNA microarray analysis revealed that MPT0L145 decreased genes associated cell cycle progression, and increased genes associated with autophagy pathway. Accordingly, the data revealed that MPT0L145 induced G0/G1 cell cycle arrest and decreased protein levels of cyclin E. Moreover, we provided the evidence that autophagy contributes to FGFR inhibitor-related cell death. Finally, MPT0L145 exhibited comparable antitumor activity to cisplatin with better safety in a RT-112 xenograft model. Taken together, these findings support the utility of MPT0L145 as a novel FGFR inhibitor, providing a strong rationale for further evaluation of this compound as a therapeutic agent for bladder cancers.",
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AU - Yen, Yun

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