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Development of the phenylpyrazolo[3,4-d]pyrimidine-based, insulin-like growth factor receptor/Src/AXL-targeting small
Ho Jin Lee1, Phuong Chi Pham2, Honglan Pei1
1Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
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 -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 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.
Insights
A novel small molecule, LL6, effectively targets insulin-like growth factor 1 receptor (IGF-1R), Src, and AXL kinases. This multitargeting approach shows significant promise in suppressing non-small cell lung cancer growth and metastasis with minimal toxicity.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The insulin-like growth factor 1 receptor (IGF-1R) signaling pathway is crucial in cancer development and progression.
- Src and AXL kinases contribute to resistance against anti-IGF-1R therapies, necessitating co-targeting strategies.
- Developing novel multitargeting anticancer drugs with reduced toxicity is essential.
Purpose of the Study:
- To synthesize and evaluate novel phenylpyrazolo[3,4-d]pyrimidine (PP)-based compounds as inhibitors of IGF-1R, Src, and AXL.
- To assess the antitumor and antimetastatic efficacy of the lead compound LL6 in preclinical cancer models.
- To determine the toxicity profile of LL6.
Main Methods:
- Synthesis of PP-based compounds conjugated with 2,4-bis-arylamino-1,3-pyrimidines (I2) via click chemistry.
- In vitro and in vivo evaluation of LL6 using MTT assays, colony formation assays, migration assays, flow cytometry, tumor xenograft models, Kras-driven lung tumorigenesis models, and metastasis models.
- Toxicity assessment of LL6 in vitro and in vivo.
Main Results:
- LL6 demonstrated potent apoptosis induction and suppressed viability and colony formation in drug-resistant non-small cell lung cancer (NSCLC) cell lines.
- LL6 inhibited NSCLC cell migration at non-toxic concentrations.
- In vivo studies showed LL6 significantly suppressed NSCLC xenograft tumor growth and Lewis lung carcinoma (LLC) allograft metastasis with favorable toxicity profiles.
- LL6 treatment substantially reduced lung tumor multiplicity, volume, and load in Kras transgenic mice.
Conclusions:
- LL6 exhibits potential as a novel small molecule kinase inhibitor targeting IGF-1R, Src, and AXL.
- LL6 represents a promising new therapeutic strategy for anticancer treatment, particularly for lung cancers.
- The multitargeting approach of LL6 offers a new avenue for overcoming therapeutic resistance and improving cancer treatment outcomes.
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