Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy
Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1<i>H</i&...
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| Format: | Article |
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MDPI AG
2020-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/23/5693 |
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| author | Lingzhi Zhang Qiurong Ju Jinjin Sun Lei Huang Shiqi Wu Shuping Wang Yin Li Zhe Guan Qihua Zhu Yungen Xu |
| author_facet | Lingzhi Zhang Qiurong Ju Jinjin Sun Lei Huang Shiqi Wu Shuping Wang Yin Li Zhe Guan Qihua Zhu Yungen Xu |
| author_sort | Lingzhi Zhang |
| collection | DOAJ |
| description | Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidine dual ERK/PI3K inhibitors. Compound <b>32d</b> was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound <b>32d</b> possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that <b>32d</b> was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors. |
| first_indexed | 2024-03-10T14:22:33Z |
| format | Article |
| id | doaj.art-a0cb71a2e42343b7bb95b5ffeb1612b0 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:22:33Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a0cb71a2e42343b7bb95b5ffeb1612b02023-11-20T23:18:16ZengMDPI AGMolecules1420-30492020-12-012523569310.3390/molecules25235693Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer TherapyLingzhi Zhang0Qiurong Ju1Jinjin Sun2Lei Huang3Shiqi Wu4Shuping Wang5Yin Li6Zhe Guan7Qihua Zhu8Yungen Xu9State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, ChinaConcomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidine dual ERK/PI3K inhibitors. Compound <b>32d</b> was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound <b>32d</b> possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that <b>32d</b> was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.https://www.mdpi.com/1420-3049/25/23/5693ERK inhibitorPI3K inhibitordual ERK/PI3K inhibitorscross-talk |
| spellingShingle | Lingzhi Zhang Qiurong Ju Jinjin Sun Lei Huang Shiqi Wu Shuping Wang Yin Li Zhe Guan Qihua Zhu Yungen Xu Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy Molecules ERK inhibitor PI3K inhibitor dual ERK/PI3K inhibitors cross-talk |
| title | Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy |
| title_full | Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy |
| title_fullStr | Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy |
| title_full_unstemmed | Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy |
| title_short | Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy |
| title_sort | discovery of novel dual extracellular regulated protein kinases erk and phosphoinositide 3 kinase pi3k inhibitors as a promising strategy for cancer therapy |
| topic | ERK inhibitor PI3K inhibitor dual ERK/PI3K inhibitors cross-talk |
| url | https://www.mdpi.com/1420-3049/25/23/5693 |
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