GZD856, a novel potent PDGFRα/β inhibitor, suppresses the growth and migration of lung cancer cells in vitro and in vivo

• Published in: Cancer letters 2016-05, Vol.375 (1), p.172-178
• Main Authors: Zhang, Zhang, Ren, Xiaomei, Lu, Xiaoyun, Wang, Deping, Hu, Xianjing, Zheng, Yi, Song, Liyan, Pang, Hongwen, Yu, Rongmin, Ding, Ke
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Benzamides - pharmacokinetics; Benzamides - pharmacology; Brain Neoplasms - prevention & control; Brain Neoplasms - secondary; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Female; GZD856; Hematology, Oncology and Palliative Medicine; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Male; Metastasis; Mice, SCID; PDGFRα/β inhibitor; Phosphorylation; Protein Processing, Post-Translational; Rats, Sprague-Dawley; Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Stromal; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2016.02.017

Highlights Lung cancer remains the leading cause of cancer death worldwide, despite of the recent significant progress on chemotherapies, immunotherapies and kinase inhibitor drugs. Inhibition of PDGFRs represents a new promising strategy for human lung cancer management by targeting both autocrine-stimulated cancer cell growth and/or recruitment of cancer-associated stromal fibroblasts (CAFs). In this paper, we report the the discovery of GZD856 as new PDGFRα/β inhibitor. 1) The compound potently inhibits the kinase activities of PDGFRα/β and dose dependently blocks the PDGFRα/β signaling pathway in lung cancer cells. 2) It strongly suppresses the proliferation of PDGRα amplified H1703 (PDGRβ- ) human lung cancer cells with an IC50 value of 0.25±0.07 µM, but is obviously less potent against PDGRα negative human lung cancer cell lines. 3) The compound displays good pharmacokinetic parameters (t1/2 = 22.2 h, Cmax = 899.5ug/L, oral bioavailability F = 78%) and demonstrates significant in vivo antitumor efficacy in xenograft mouse models of H1703 cancer cells. 4) It also inhibits the in vivo growth and metastasis events of A549 cancer cells in both xenograft and allograft models through the blockage of PDGFR mediated stromal-cancer cell interaction. Thus, GZD856 may serve as a new promising candidate for anti-lung cancer drug development.