Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors
Introduction: Phosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting PI3Kα have attracted c...
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Elsevier
2025-02-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123224000894 |
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| author | Changqun Liu Yuening Cao Yi Zuo Chaozheng Zhang Senmiao Ren Xin Zhang Chuanqi Wang Yingjie Zeng Jie Ling Yilan Liu Zixian Chen Xiujun Cao Zhengzhi Wu Chuantao Zhang Jun Lu |
| author_facet | Changqun Liu Yuening Cao Yi Zuo Chaozheng Zhang Senmiao Ren Xin Zhang Chuanqi Wang Yingjie Zeng Jie Ling Yilan Liu Zixian Chen Xiujun Cao Zhengzhi Wu Chuantao Zhang Jun Lu |
| author_sort | Changqun Liu |
| collection | DOAJ |
| description | Introduction: Phosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting PI3Kα have attracted considerable interest in recent years. Molecular hybridization, with the advantage of simplified pharmacokinetics and drug-drug interactions, emerged as one of the important avenues for discovering potential drugs. Objectives: This study aimed to construct PI3Kα inhibitors by hybridization and investigate their antitumor activity and mechanism. Methods: 26 quinazoline-2-indolinone derivatives were obtained by molecular hybridization, and their structure–activity relationship was analyzed by MTT, in vitro kinase activity and molecular docking. The biological evaluation of compound 8 was performed by transwell, flow cytometry, laser scanning confocal microscopy, Western blot, CTESA and immunohistochemistry. Results: Here, we employed molecular hybridization methods to construct a series of quinazoline-2-indolinone derivatives as PI3Kα selective inhibitors. Encouragingly, representative compound 8 exhibited a PI3Kα enzymatic IC50 value of 9.11 nM and 10.41/16.99/37.53-fold relative to the biochemical selectivity for PI3Kβ/γ/δ, respectively. Moreover, compound 8 effectively suppressed the viability of B16, HCT116, MCF-7, H22, PC-3, and A549 cells (IC50 values: 0.2 μM ∼ 0.98 μM), and dramatically inhibited the proliferation and migration of NSCLC cells, as well as induced mitochondrial apoptosis through the PI3K/Akt/mTOR pathway. Importantly, compound 8 demonstrated potent in vivo anti-tumor activity in non-small cell lung cancer mouse models without visible toxicity. Conclusions: This study presented a new avenue for the development of PI3Kα inhibitors and provided a solid foundation for novel QHIDs as potential future therapies for the treatment of NSCLC. |
| format | Article |
| id | doaj-art-ebd8006bfd554de6aae8fc34d45a9c18 |
| institution | Kabale University |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj-art-ebd8006bfd554de6aae8fc34d45a9c182025-01-18T05:04:22ZengElsevierJournal of Advanced Research2090-12322025-02-0168459475Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitorsChangqun Liu0Yuening Cao1Yi Zuo2Chaozheng Zhang3Senmiao Ren4Xin Zhang5Chuanqi Wang6Yingjie Zeng7Jie Ling8Yilan Liu9Zixian Chen10Xiujun Cao11Zhengzhi Wu12Chuantao Zhang13Jun Lu14State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaHematology Department, The General Hospital of the Western Theater Command PLA, Chengdu 610081, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaState Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Corresponding authors at: State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China (Jun Lu, Xiujun Cao); Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China (Chuantao Zhang); The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China (Zhengzhi Wu).The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China; Corresponding authors at: State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China (Jun Lu, Xiujun Cao); Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China (Chuantao Zhang); The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China (Zhengzhi Wu).Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Corresponding authors at: State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China (Jun Lu, Xiujun Cao); Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China (Chuantao Zhang); The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China (Zhengzhi Wu).State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Corresponding authors at: State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China (Jun Lu, Xiujun Cao); Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China (Chuantao Zhang); The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China (Zhengzhi Wu).Introduction: Phosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting PI3Kα have attracted considerable interest in recent years. Molecular hybridization, with the advantage of simplified pharmacokinetics and drug-drug interactions, emerged as one of the important avenues for discovering potential drugs. Objectives: This study aimed to construct PI3Kα inhibitors by hybridization and investigate their antitumor activity and mechanism. Methods: 26 quinazoline-2-indolinone derivatives were obtained by molecular hybridization, and their structure–activity relationship was analyzed by MTT, in vitro kinase activity and molecular docking. The biological evaluation of compound 8 was performed by transwell, flow cytometry, laser scanning confocal microscopy, Western blot, CTESA and immunohistochemistry. Results: Here, we employed molecular hybridization methods to construct a series of quinazoline-2-indolinone derivatives as PI3Kα selective inhibitors. Encouragingly, representative compound 8 exhibited a PI3Kα enzymatic IC50 value of 9.11 nM and 10.41/16.99/37.53-fold relative to the biochemical selectivity for PI3Kβ/γ/δ, respectively. Moreover, compound 8 effectively suppressed the viability of B16, HCT116, MCF-7, H22, PC-3, and A549 cells (IC50 values: 0.2 μM ∼ 0.98 μM), and dramatically inhibited the proliferation and migration of NSCLC cells, as well as induced mitochondrial apoptosis through the PI3K/Akt/mTOR pathway. Importantly, compound 8 demonstrated potent in vivo anti-tumor activity in non-small cell lung cancer mouse models without visible toxicity. Conclusions: This study presented a new avenue for the development of PI3Kα inhibitors and provided a solid foundation for novel QHIDs as potential future therapies for the treatment of NSCLC.http://www.sciencedirect.com/science/article/pii/S2090123224000894Molecular hybridizationQuinazoline2-indolinonePI3Kα inhibitorNon-small cell lung cancer |
| spellingShingle | Changqun Liu Yuening Cao Yi Zuo Chaozheng Zhang Senmiao Ren Xin Zhang Chuanqi Wang Yingjie Zeng Jie Ling Yilan Liu Zixian Chen Xiujun Cao Zhengzhi Wu Chuantao Zhang Jun Lu Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors Journal of Advanced Research Molecular hybridization Quinazoline 2-indolinone PI3Kα inhibitor Non-small cell lung cancer |
| title | Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors |
| title_full | Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors |
| title_fullStr | Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors |
| title_full_unstemmed | Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors |
| title_short | Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors |
| title_sort | hybridization based discovery of novel quinazoline 2 indolinone derivatives as potent and selective pi3kα inhibitors |
| topic | Molecular hybridization Quinazoline 2-indolinone PI3Kα inhibitor Non-small cell lung cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224000894 |
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