Development of a 4-aminopyrazolo[3,4-d]pyrimidine-based dual IGF1R/Src inhibitor as a novel anticancer agent with minimal toxicity

• Published in: Molecular cancer 2018-02, Vol.17 (1), p.50-50, Article 50
• Main Authors: Lee, Ho Jin, Pham, Phuong Chi, Hyun, Seung Yeob, Baek, Byungyeob, Kim, Byungjin, Kim, Yunha, Min, Hye-Young, Lee, Jeeyeon, Lee, Ho-Young
• Format: Article
• Language: English
• Subjects: Analysis; Apoptosis - drug effects; Carcinoma, Non-Small-Cell Lung - drug therapy; Care and treatment; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Dasatinib - therapeutic use; Drug resistance; Humans; Imidazoles - therapeutic use; Immunohistochemistry; Lung cancer; MCF-7 Cells; Pyrazines - therapeutic use; Pyrimidines - chemistry; Pyrimidines - therapeutic use; Receptor, IGF Type 1; Receptors, Somatomedin - antagonists & inhibitors; Receptors, Somatomedin - metabolism; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-018-0802-4

Both the type I insulin-like growth factor receptor (IGF1R) and Src pathways are associated with the development and progression of numerous types of human cancer, and Src activation confers resistance to anti-IGF1R therapies. Hence, targeting both IGF1R and Src concurrently is one of the main challenges in combating resistance to the currently available anti-IGF1R-based anticancer therapies. However, the enhanced toxicity from this combinatorial treatment could be one of the main hurdles for this strategy, suggesting the necessity of developing a novel strategy for co-targeting IGF1R and Src to meet an urgent clinical need. We synthesized a series of 4-aminopyrazolo[3,4-d]pyrimidine-based dual IGF1R/Src inhibitors, selected LL28 as an active compound and evaluated its potential antitumor effects in vitro and in vivo using the MTT assay, colony formation assays, flow cytometric analysis, a tumor xenograft model, and the Kras -driven spontaneous lung tumorigenesis model. LL28 markedly suppressed the activation of IGF1R and Src and significantly inhibited the viability of several NSCLC cell lines in vitro by inducing apoptosis. Administration of mice with LL28 significantly suppressed the growth of H1299 NSCLC xenograft tumors without overt toxicity and substantially reduced the multiplicity, volume, and load of lung tumors in the Kras -driven lung tumorigenesis model. The present results suggest the potential of LL28 as a novel anticancer drug candidate targeting both IGF1R and Src, providing a new avenue to efficient anticancer therapies. Further investigation is warranted in advanced preclinical and clinical settings.