Page 14 - H. Cell signaling

[H. Cell signaling-8]

Development of a IGF-1R/Src/Axl inhibitor as a novel

anticancer agent with reduced toxicity

Ho Jin Lee¹˙#, Hye-Young Min¹, Hong Lan Pei¹, Ho-Young Lee¹˙*

¹college of pharmacy, Seoul National University, Seoul 08826, Republic of Korea

Lung cancer is the leading cause of cancer-related deaths in the world. Despite advances in anticancer therapeutics
for patients with lung cancer, lung cancer still has a poor prognosis. Both the type I insulin-like growth factor
receptor (IGF-1R) and Src pathways are associated with the development and progression of numerous types of

human cancer including lung cancer. In addition, Src activation is associated with resistance to anti-IGF-1R therapies,

and Axl is upregulated by pharmacological blockade of Src. Therefore, targeting IGF-1R, Src, and Axl is expected to
exhibit potent antitumor efficacy by overcoming drug resistance. However, the clinical use of this strategy may be
limited due to potential toxicity. To develop a novel multitarget kinase inhibitor with minimal toxicity, we synthesized

compound 6 and evaluated its antitumor and antimetastatic effects. Compound 6 inhibited the viability of several
NSCLC cell lines by inducing apoptosis. Compound 6 significantly inhibited the growth of primary NSCLC xenograft

tumors and mutant Kras-driven lung tumorigenesis by suppressing the activation of IGF-1R, Src and Axl. These
results suggest the potential of compound 6 as a novel anticancer multitarget kinase inhibitor, providing a new

avenue to efficient anticancer therapies.