A novel ALK inhibitor ZYY inhibits Karpas299 cell growth in vitro and in a mouse xenograft model and induces protective autophagy

Shen, Jiwei; Wang, Junfang; Du, Jianan; Wang, Lijing; Zhou, Xuejiao; Chang, Xing; Li, Zengqiang; Zhai, Xin; Wu, Yingliang

doi:10.1016/j.taap.2019.114781

Cited by 8 publications

(5 citation statements)

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“…The effects of target compounds 6a–6x , colchicines, and SMART on cell viability in vitro were performed by the MTT assay as previously described ( 37 ).…”

Section: Methodsmentioning

confidence: 99%

A novel tubulin inhibitor, 6h, suppresses tumor-associated angiogenesis and shows potent antitumor activity against non–small cell lung cancers

Huang

Zhou

et al. 2022

Journal of Biological Chemistry

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“…The effects of target compounds 6a–6x , colchicines, and SMART on cell viability in vitro were performed by the MTT assay as previously described ( 37 ).…”

Section: Methodsmentioning

confidence: 99%

A novel tubulin inhibitor, 6h, suppresses tumor-associated angiogenesis and shows potent antitumor activity against non–small cell lung cancers

Huang

Zhou

et al. 2022

Journal of Biological Chemistry

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“…To investigate the functional consequence of inhibiting ALK in cells, five cancer cell lines (H3122, H2228, H1299, A549, and Hela) were treated with the compounds at different concentrations, and the growth was monitored through the MTT assay (Table S2). Among the cell lines, H3122 and H2228 were reported as ALK-positive human NSCLC cell lines. , As despicted in Figure b, five of the compounds displayed potent antiproliferative activities ( Con A-1 , Con A-3 , Con A-4 , Con B-1 , and Con B-3 ), and four of them showed advantaged bioactivity compared with Ceritinib (Figure c).…”

Section: Resultsmentioning

confidence: 99%

“…Among the cell lines, H3122 and H2228 were reported as ALK-positive human NSCLC cell lines. 19,21 As despicted in Figure 3b, five of the compounds displayed potent antiproliferative activities (Con A-1, Con A-3, Con A-4, Con B-1, and Con B-3), and four of them showed advantaged bioactivity compared with Ceritinib (Figure 3c).…”

Section: ■ Introductionmentioning

confidence: 94%

Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

Yan

Zhong

et al. 2021

J. Med. Chem.

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Potent inhibitors of ALK are highly desired because of the occurrence of drug resistance. We herein firstly report the development of a rationally designed inhibitor, Con B-1, which can covalently bind to Cys1259, a cysteine located outside the ALK active site by linking a warhead with Ceritinib through a 2,2′-Oxybis(ethylamine) linker. The in vitro and in vivo assays showed ConB-1 is a potent selective ALKi with low toxicity to normal cells. In addition, the molecule showed significant improvement of anticancer activities and potential antidrug resistant activity compared with Ceritinib, demonstrating the covalent inhibitor of ALK can be a promising drug candidate for the treatment of NSCLC. This work may provide a novel perspective on the design of covalent inhibitors.

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“…After incubation with primary/secondary Abs and sufficient washing, the bands were visualized and detected utilizing an ECL agent. The densitometry analysis was carried out using ImageJ2 software 25 …”

Section: Methodsmentioning

confidence: 99%

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

et al. 2020

Cancer Science

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Both ceritinib (CER) and programmed cell death (PD)‐1/PD ligand‐1 (PD‐L1) have brought significant breakthroughs for anaplastic lymphoma kinase (ALK)‐rearranged non‐small‐cell lung cancer (NSCLC). However, the overall clinical efficacy of either CER or PD‐1/PD‐L1 inhibitor monotherapy has been limited to a large extent. In addition, the antitumor effect of combined CER and PD‐L1 inhibitor in ALK‐rearranged NSCLC is not fully understood. In H2228 cells, we examined the tumor killing effect of CER plus PD‐L1 inhibitor in vitro by quantitative RT‐PCR, flow cytometry, ELISA, western blot analysis, PBMC coculture system, and plasmid and transfection experiments. A Ba/F3 (EML4‐ALK‐WT) xenograft mouse model was also utilized to further evaluate the synergistic anticancer effects of CER and PD‐L1 inhibitor in vivo. The coculture system of PBMCs with H2228 cells promotes the expression of PD‐L1 and phospho‐ERK, and combined treatments facilitate lymphocyte proliferation and activation, inhibit PD‐L1 expression, and enhance lymphocyte cytotoxicity and cell death. In the in vivo NSCLC xenograft model, the volumes of tumors treated with CER and PD‐L1 inhibitor in combination were significantly smaller than those treated with CER or PD‐L1 alone. The relative tumor growth inhibitions were 84.9%, 20.0%, and 91.9% for CER, PD‐L1 inhibitor, and CER plus PD‐L1 groups, respectively. Ceritinib could synergize with PD‐1/PD‐L1 blockade to yield enhanced antitumor responses along with favorable tolerability of adverse effects. Ceritinib and PD‐L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provides a key insight and proof of principle for evaluating CER plus PD‐L1 blockade as combination therapy in clinical therapeutic practice.

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A novel ALK inhibitor ZYY inhibits Karpas299 cell growth in vitro and in a mouse xenograft model and induces protective autophagy

Cited by 8 publications

References 50 publications

A novel tubulin inhibitor, 6h, suppresses tumor-associated angiogenesis and shows potent antitumor activity against non–small cell lung cancers

A novel tubulin inhibitor, 6h, suppresses tumor-associated angiogenesis and shows potent antitumor activity against non–small cell lung cancers

Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

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