Novel Dual-Target Kinase Inhibitors of EGFR and ALK Were Designed, Synthesized, and Induced Cell Apoptosis in Non-Small Cell Lung Cancer

Fan, Yangyang; Wei, Li; Nie, Wenyan; Yao, Han; Ren, Yuanyuan; Wang, Mengxuan; Nie, Haoran; Gu, Chenxi; Liu, Jiadai; An, Baijiao

doi:10.3390/molecules28052006

Cited by 4 publications

(2 citation statements)

References 37 publications

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“…Phase 1/2 clinical trial (NCT05384626) will evaluate doselimiting toxicities, dosage, and ORR in ALK-positive advanced/ metastatic NSCLC or other solid tumors (Inc, 2022). Furthermore, recent studies report several novel compounds/agents capable of inhibiting ALK (Wang et al, 2022;Cao et al, 2023;Fan et al, 2023).…”

Section: Novel Anaplastic Lymphoma Kinase Inhibitorsmentioning

confidence: 99%

Anaplastic lymphoma kinase inhibitors—a review of anticancer properties, clinical efficacy, and resistance mechanisms

Kiełbowski,

Żychowska,

Becht

2023

Front. Pharmacol.

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Fusions and mutations of anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, have been identified in several neoplastic diseases. Rearranged ALK is a driver of tumorigenesis, which activates various signaling pathway associated with proliferation and survival. To date, several agents that target and inhibit ALK have been developed. The most studied ALK-positive disease is non-small cell lung cancer, and three generations of ALK tyrosine kinase inhibitors (TKIs) have been approved for the treatment of metastatic disease. Nevertheless, the use of ALK-TKIs is associated with acquired resistance (resistance mutations, bypass signaling), which leads to disease progression and may require a substitution or introduction of other treatment agents. Understanding of the complex nature and network of resistance mutations may allow to introduce sequential and targeted therapies. In this review, we aim to summarize the efficacy and safety profile of ALK inhibitors, describe off-target anticancer effects, and discuss resistance mechanisms in the context of personalized oncology.

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Section: Novel Anaplastic Lymphoma Kinase Inhibitorsmentioning

confidence: 99%

Anaplastic lymphoma kinase inhibitors—a review of anticancer properties, clinical efficacy, and resistance mechanisms

Kiełbowski,

Żychowska,

Becht

2023

Front. Pharmacol.

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“…Among various studies on fourth-generation EGFR triple mutation inhibitors, Lee et al reported a class of N2 and N4 diphenylpyridine-2,4-diamine derivatives containing a methanesulfonamide moiety, such as compound 25 (Figure 1), which exhibited good activity in inhibiting EGFR triple mutations in tumor cells, and thus worthy of further study [32] . In drug discovery structure activity relationship studies, small structural changes often lead to signi cant changes in activity.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of novel EGFR kinase inhibitors for the treatment of EGFR C797S mutation in non-small cell lung cancer

Nie,

Wang,

Xia

et al. 2024

Preprint

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Third-generation cutaneous growth factor receptor tyrosine kinase inhibitors have led to impressive advances in the treatment of non-small cell lung cancer. However, acquired resistance significantly limits the clinical application of these agents, with the epidermal growth factor receptor (EGFR)C797S mutation being the primary resistance mechanism. In this study, a series of novel EGFR kinase inhibitors was designed and synthesized for the treatment of the EGFRC797S mutation in non-small cell lung cancer. Structure activity relationship screening revealed that compound 5d was the most effective inhibitor of the C797S mutation. It strongly inhibited Baf3-EGFRL858R/T790M/C797S and Baf3-EGFR 19del/T790M/C797S cell lines, with IC50 values of 0.01836±0.0065 and 0.025±0.005 μM, respectively. Molecular docking studies showed that 5d binds to the EGFRL858R/T790M/C797S and EGFR19del/T790M/C797S proteins effectively. A mechanistic study showed that 5d induced cell cycle arrest in the G2/M phase. Compound 5d caused cell apoptosis in a dose-dependent manner, accompanied by a significant increase in the level of the apoptotic protein cleaved caspase-3. An in vivo xenograft assay of mice with Baf3-EGFR19del/T790M/C797S cells showed that 5d effectively inhibited tumor growth, with inhibition rates of 45.2% (70 mg/kg) and 55.7% (100 mg/kg) being observed. Therefore, 5d is worthy of further investigation as a fourth-generation EGFR inhibitor.

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Covalent Epidermal Growth Factor Receptor (EGFR) Inhibitors in Targeted Therapy of Drug-Resistant Non-Small Cell Lung Cancer (A Review)

Shvetsov,

Semenov

2024

Russ J Bioorg Chem

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Novel Dual-Target Kinase Inhibitors of EGFR and ALK Were Designed, Synthesized, and Induced Cell Apoptosis in Non-Small Cell Lung Cancer

Cited by 4 publications

References 37 publications

Anaplastic lymphoma kinase inhibitors—a review of anticancer properties, clinical efficacy, and resistance mechanisms

Anaplastic lymphoma kinase inhibitors—a review of anticancer properties, clinical efficacy, and resistance mechanisms

Design and synthesis of novel EGFR kinase inhibitors for the treatment of EGFR C797S mutation in non-small cell lung cancer

Covalent Epidermal Growth Factor Receptor (EGFR) Inhibitors in Targeted Therapy of Drug-Resistant Non-Small Cell Lung Cancer (A Review)

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