Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line
Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d...
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MDPI AG
2020-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/1/9 |
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| author | Ranza Elrayess Yasmine M. Abdel Aziz Mohamed Saleh Elgawish Marwa Elewa Asmaa S. A. Yassen Sameh S. Elhady Hosam A. Elshihawy Mohamed M. Said |
| author_facet | Ranza Elrayess Yasmine M. Abdel Aziz Mohamed Saleh Elgawish Marwa Elewa Asmaa S. A. Yassen Sameh S. Elhady Hosam A. Elshihawy Mohamed M. Said |
| author_sort | Ranza Elrayess |
| collection | DOAJ |
| description | Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC<sub>50</sub> values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (<b>2</b>) at 40 µM. Of the synthesized compounds, 2-(1<i>H</i>-pyrazolo[3,4-b]pyridin-3-ylamino)-<i>N</i>-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (<b>21a</b>) achieved the highest in vitro cytotoxic activity against H1299, with an IC<sub>50</sub> value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC<sub>50</sub> of the approved drug imatinib (<b>1</b>). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (<b>21a</b>) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2. |
| first_indexed | 2024-03-10T13:48:09Z |
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| id | doaj.art-204365c8ec4948bdb85853c9ee4b9a7e |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T13:48:09Z |
| publishDate | 2020-12-01 |
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| spelling | doaj.art-204365c8ec4948bdb85853c9ee4b9a7e2023-11-21T02:21:33ZengMDPI AGPharmaceuticals1424-82472020-12-01141910.3390/ph14010009Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell LineRanza Elrayess0Yasmine M. Abdel Aziz1Mohamed Saleh Elgawish2Marwa Elewa3Asmaa S. A. Yassen4Sameh S. Elhady5Hosam A. Elshihawy6Mohamed M. Said7Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptMedicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptDepartment of Natural Products, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptPharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, EgyptDual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC<sub>50</sub> values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (<b>2</b>) at 40 µM. Of the synthesized compounds, 2-(1<i>H</i>-pyrazolo[3,4-b]pyridin-3-ylamino)-<i>N</i>-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (<b>21a</b>) achieved the highest in vitro cytotoxic activity against H1299, with an IC<sub>50</sub> value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC<sub>50</sub> of the approved drug imatinib (<b>1</b>). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (<b>21a</b>) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.https://www.mdpi.com/1424-8247/14/1/9thieno[2,3-d][1,2,3]triazineacetamideH1299HER2EGFR |
| spellingShingle | Ranza Elrayess Yasmine M. Abdel Aziz Mohamed Saleh Elgawish Marwa Elewa Asmaa S. A. Yassen Sameh S. Elhady Hosam A. Elshihawy Mohamed M. Said Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line Pharmaceuticals thieno[2,3-d][1,2,3]triazine acetamide H1299 HER2 EGFR |
| title | Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line |
| title_full | Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line |
| title_fullStr | Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line |
| title_full_unstemmed | Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line |
| title_short | Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line |
| title_sort | discovery of potent dual egfr her2 inhibitors based on thiophene scaffold targeting h1299 lung cancer cell line |
| topic | thieno[2,3-d][1,2,3]triazine acetamide H1299 HER2 EGFR |
| url | https://www.mdpi.com/1424-8247/14/1/9 |
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