Antiproliferative Activity of a New Quinazolin-4(3H)-One Derivative via Targeting Aurora Kinase A in Non-Small Cell Lung Cancer.
Antiproliferative Activity of a New Quinazolin-4(3H)-One Derivative via Targeting Aurora Kinase A in Non-Small Cell Lung Cancer.
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新型 Quinazolin-4(3H)-One 衍生物通过靶向 Aurora 激酶 A 对非小细胞肺癌的抗增殖活性
DOI：
10.3390/ph15060698
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发表时间：
2022-06-02
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影响因子：
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非小细胞肺癌(NSCLC)是最常见的肺癌亚型。虽然非小细胞肺癌的治疗采用化疗和靶向治疗，但存活率仍然很低。最近的研究结果表明，细胞周期调节因子极光激酶A(AKA)是非小细胞肺癌治疗的潜在靶点。此前，我们报道了喹唑啉-4(~3H)-酮的化学实体代表了AKA抑制剂的新模板，具有抗肿瘤细胞增殖的活性。进一步设计合成了喹唑啉-4(~3H)-酮衍生物，以改善其对非小细胞肺癌细胞的药代动力学性质和抗增殖活性。衍生物BIQO-19(6-(4-oxo-3-(pyrimidin-2-ylmethyl)-3，4-dihydroquinazolin-6-yl)imidazo[1，2-a]吡啶-2-羧酸乙酯)在非小细胞肺癌细胞中表现出更好的溶解性和抗增殖活性，包括表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)抗性的非小细胞肺癌细胞。BIQO-19能有效抑制耐EGFR-TKI的H1975非小细胞肺癌细胞的生长，并抑制这些细胞中活化的AKA(p-AKA)的表达。BIQO-19对AKA的抑制可显著诱导H1975细胞发生G2/M期阻滞，进而诱导细胞凋亡。此外，吉非替尼与BIQO-19联合应用对非小细胞肺癌细胞具有协同抗增殖活性。这些发现表明，BIQO-19有可能作为一种新的治疗剂来恢复EGFR-TKI耐药的NSCLC细胞对吉非替尼的敏感性。
Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype. Although chemotherapy and targeted therapy are used for the treatment of patients with NSCLC, the survival rate remains very low. Recent findings suggested that aurora kinase A (AKA), a cell cycle regulator, is a potential target for NSCLC therapy. Previously, we reported that a chemical entity of quinazolin-4(3H)-one represents a new template for AKA inhibitors, with antiproliferative activity against cancer cells. A quinazolin-4(3H)-one derivative was further designed and synthesized in order to improve the pharmacokinetic properties and antiproliferation activity against NSCLC cell lines. The derivative, BIQO-19 (Ethyl 6-(4-oxo-3-(pyrimidin-2-ylmethyl)-3,4-dihydroquinazolin-6-yl)imidazo [1,2-a]pyridine-2-carboxylate), exhibited improved solubility and antiproliferative activity in NSCLC cells, including epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI)-resistant NSCLC cells. BIQO-19 effectively inhibited the growth of the EGFR-TKI-resistant H1975 NSCLC cells, with the suppression of activated AKA (p-AKA) expression in these cells. The inhibition of AKA by BIQO-19 significantly induced G2/M phase arrest and subsequently evoked apoptosis in H1975 cells. In addition, the combination of gefitinib and BIQO-19 exhibited synergistic antiproliferative activity in NSCLC cells. These findings suggest the potential of BIQO-19 as a novel therapeutic agent for restoring the sensitivity of gefitinib in EGFR-TKI-resistant NSCLC cells.
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DOI：
10.1158/1078-0432.ccr-08-1455
发表时间：
2008-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
Costa DB;Nguyen KS;Cho BC;Sequist LV;Jackman DM;Riely GJ;Yeap BY;Halmos B;Kim JH;Jänne PA;Huberman MS;Pao W;Tenen DG;Kobayashi S
通讯作者：
Kobayashi S
影响因子：
3.4
作者：
Chu, Quincy Siu-chung;Bouganim, Nathaniel;Batist, Gerald
通讯作者：
Batist, Gerald
影响因子：
37.3
作者：
Dos Santos EO;Carneiro-Lobo TC;Aoki MN;Levantini E;Bassères DS
通讯作者：
Bassères DS
影响因子：
2.9
作者：
Doan Thanh Hieu;Duong Tien Anh;Nguyen-Hai Nam
通讯作者：
Nguyen-Hai Nam
影响因子：
3.4
作者：
Ke, Yi-Yu;Shiao, Hui-Yi;Hsieh, Hsing-Pang
通讯作者：
Hsieh, Hsing-Pang