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Theranostics 2021; 11(4):1918-1936. doi:10.7150/thno.48865 This issue Cite

Research Paper

Development of the phenylpyrazolo[3,4-d]pyrimidine-based, insulin-like growth factor receptor/Src/AXL-targeting small molecule kinase inhibitor

Ho Jin Lee¹, Phuong Chi Pham², Honglan Pei¹, Bumhee Lim², Seung Yeob Hyun¹, Byungyeob Baek², Byungjin Kim², Yunha Kim², Min-Hwan Kim², Nae-Won Kang², Hye-Young Min^1,2, Dae-Duk Kim², Jeeyeon Lee^2✉, Ho-Young Lee^1,2✉

1. Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.

✉ Corresponding authors: Ho-Young Lee, Ph.D., Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Phone: +82-2-880-9277; Fax: +82-2-6280-5327; E-mail: hylee135ac.kr; Jeeyeon Lee, Ph.D., College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; Tel: +82-2-880-2471; Fax: +82-2-884-8334; E-mail: jyleeutac.kr. More

Abstract

Rationale: The type I insulin-like growth factor receptor (IGF-1R) signaling pathway plays key roles in the development and progression of numerous types of human cancers, and Src and AXL have been found to confer resistance to anti-IGF-1R therapies. Hence, co-targeting Src and AXL may be an effective strategy to overcome resistance to anti-IGF-1R therapies. However, pharmacologic targeting of these three kinases may result in enhanced toxicity. Therefore, the development of novel multitarget anticancer drugs that block IGF-1R, Src, and AXL is urgently needed.

Methods: We synthesized a series of phenylpyrazolo[3,4-d]pyrimidine (PP)-based compounds, wherein the PP module was conjugated with 2,4-bis-arylamino-1,3-pyrimidines (I2) via a copper(I)-catalyzed alkyne-azide cycloaddition reaction. To develop IGF-1R/Src/AXL-targeting small molecule kinase inhibitors, we selected LL6 as an active compound and evaluated its antitumor and antimetastatic effects in vitro and in vivo using the MTT assay, colony formation assays, migration assay, flow cytometric analysis, a tumor xenograft model, the Kras^G12D/+-driven spontaneous lung tumorigenesis model, and a spontaneous metastasis model using Lewis lung carcinoma (LLC) allografts. We also determined the toxicity of LL6 in vitro and in vivo.

Results: LL6 induced apoptosis and suppressed viability and colony-forming capacities of various non-small cell lung cancer (NSCLC) cell lines and their sublines with drug resistance. LL6 also suppressed the migration of NSCLC cells at nontoxic doses. Administration of LL6 in mice significantly suppressed the growth of NSCLC xenograft tumors and metastasis of LLC allograft tumors with outstanding toxicity profiles. Furthermore, the multiplicity, volume, and load of lung tumors in Kras^G12D/+ transgenic mice were substantially reduced by the LL6 treatment.

Conclusions: Our results show the potential of LL6 as a novel IGF-1R/Src/AXL-targeting small molecule kinase inhibitor, providing a new avenue for anticancer therapies.

Keywords: small molecule kinase inhibitor, type I insulin-like growth factor receptor, Src, AXL

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