Research Papers:

Trichlorobenzene-substituted azaaryl compounds as novel FGFR inhibitors exhibiting potent antitumor activity in bladder cancer cells in vitro and in vivo

Chun-Han Chen, Yi-Min Liu, Shiow-Lin Pan, Yun-Ru Liu, Jing-Ping Liou and Yun Yen _

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Oncotarget. 2016; 7:26374-26387. https://doi.org/10.18632/oncotarget.8380

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Chun-Han Chen1, Yi-Min Liu2, Shiow-Lin Pan3, Yun-Ru Liu4, Jing-Ping Liou2,*, Yun Yen3,*

1Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

2College of Pharmacy, Taipei Medical University, Taipei, Taiwan

3The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

4Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Yun Yen, email: [email protected]

Jing-Ping Liou, email: [email protected]

Keywords: FGFR, bladder cancer, autophagy, cell cycle, FGFR3-TACC3

Received: December 10, 2015     Accepted: March 14, 2016     Published: March 25, 2016


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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