Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 Inhibitors
<b>Background/Objectives:</b> The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new seri...
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MDPI AG
2025-07-01
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| author | Fatemah S. Albalawi Mashooq A. Bhat Ahmed H. Bakheit A. F. M. Motiur Rahman Nawaf A. Alsaif Alan M. Jones Isolda Romero-Canelon |
| author_facet | Fatemah S. Albalawi Mashooq A. Bhat Ahmed H. Bakheit A. F. M. Motiur Rahman Nawaf A. Alsaif Alan M. Jones Isolda Romero-Canelon |
| author_sort | Fatemah S. Albalawi |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, <b>6</b>–<b>24</b> (<b>a</b>,<b>b</b>), as anticancer agents targeting EGFR and HER2 kinases. <b>Methods:</b> The proposed compounds were initially screened in silico using molecular docking to investigate their binding affinity to the active sites of EGFR and HER2 kinase domains. Subsequently, the compounds were synthesized and evaluated in vitro for their antiproliferative activity, using the MTT assay, against the various cancer cell lines A549, SKOV-3, A2780, and SKBR-3, with lapatinib as the reference drug. The most active derivatives were then examined to determine their inhibitory activity against EGFR and HER2 kinases. <b>Results:</b> Among the assessed compounds, significant antiproliferative activity was demonstrated by <b>19a</b>, <b>16b</b>, and <b>22b</b>. <b>19a</b> exhibited substantial anticancer efficacy against A549 and SKBR-3, with IC<sub>50</sub> values of 0.81 µM and 1.41 µM, respectively. This activity surpassed lapatinib, which has an IC<sub>50</sub> of 11.57 µM on A549 and 8.54 µM on SKBR-3 cells. Furthermore, <b>19a</b>, <b>16b</b>, and <b>22b</b> exhibited superior EGFR inhibitory efficacy compared with lapatinib (IC<sub>50</sub> = 0.13 µM), with IC<sub>50</sub> values of 0.08, 0.06, and 0.07 µM, respectively. Regarding HER2, <b>22b</b> demonstrated the greatest potency with an IC<sub>50</sub> of 0.03 µM, equipotent to lapatinib (IC<sub>50</sub> = 0.03 µM). Flow cytometry analysis of A549 cells treated with <b>19a</b> and <b>22b</b> indicated their ability to arrest the cell cycle during the G1 phase and to trigger cellular apoptosis. <b>Conclusions:</b> Compounds <b>19a</b>, <b>16b</b>, and <b>22b</b> represent intriguing candidates for the development of an anticancer agent targeting EGFR and HER2 kinases. |
| format | Article |
| id | doaj-art-74b4808f2b3a47b1bca536c12d9ac5b3 |
| institution | Kabale University |
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| spelling | doaj-art-74b4808f2b3a47b1bca536c12d9ac5b32025-08-20T03:56:46ZengMDPI AGPharmaceuticals1424-82472025-07-01187105110.3390/ph18071051Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 InhibitorsFatemah S. Albalawi0Mashooq A. Bhat1Ahmed H. Bakheit2A. F. M. Motiur Rahman3Nawaf A. Alsaif4Alan M. Jones5Isolda Romero-Canelon6School of Pharmacy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UKDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaSchool of Pharmacy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UKSchool of Pharmacy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK<b>Background/Objectives:</b> The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, <b>6</b>–<b>24</b> (<b>a</b>,<b>b</b>), as anticancer agents targeting EGFR and HER2 kinases. <b>Methods:</b> The proposed compounds were initially screened in silico using molecular docking to investigate their binding affinity to the active sites of EGFR and HER2 kinase domains. Subsequently, the compounds were synthesized and evaluated in vitro for their antiproliferative activity, using the MTT assay, against the various cancer cell lines A549, SKOV-3, A2780, and SKBR-3, with lapatinib as the reference drug. The most active derivatives were then examined to determine their inhibitory activity against EGFR and HER2 kinases. <b>Results:</b> Among the assessed compounds, significant antiproliferative activity was demonstrated by <b>19a</b>, <b>16b</b>, and <b>22b</b>. <b>19a</b> exhibited substantial anticancer efficacy against A549 and SKBR-3, with IC<sub>50</sub> values of 0.81 µM and 1.41 µM, respectively. This activity surpassed lapatinib, which has an IC<sub>50</sub> of 11.57 µM on A549 and 8.54 µM on SKBR-3 cells. Furthermore, <b>19a</b>, <b>16b</b>, and <b>22b</b> exhibited superior EGFR inhibitory efficacy compared with lapatinib (IC<sub>50</sub> = 0.13 µM), with IC<sub>50</sub> values of 0.08, 0.06, and 0.07 µM, respectively. Regarding HER2, <b>22b</b> demonstrated the greatest potency with an IC<sub>50</sub> of 0.03 µM, equipotent to lapatinib (IC<sub>50</sub> = 0.03 µM). Flow cytometry analysis of A549 cells treated with <b>19a</b> and <b>22b</b> indicated their ability to arrest the cell cycle during the G1 phase and to trigger cellular apoptosis. <b>Conclusions:</b> Compounds <b>19a</b>, <b>16b</b>, and <b>22b</b> represent intriguing candidates for the development of an anticancer agent targeting EGFR and HER2 kinases.https://www.mdpi.com/1424-8247/18/7/1051cancerEGFRHER2EGFR- and HER2-driven cancerspurine/hydrazone-containing compoundslapatinib |
| spellingShingle | Fatemah S. Albalawi Mashooq A. Bhat Ahmed H. Bakheit A. F. M. Motiur Rahman Nawaf A. Alsaif Alan M. Jones Isolda Romero-Canelon Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 Inhibitors Pharmaceuticals cancer EGFR HER2 EGFR- and HER2-driven cancers purine/hydrazone-containing compounds lapatinib |
| title | Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 Inhibitors |
| title_full | Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 Inhibitors |
| title_fullStr | Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 Inhibitors |
| title_full_unstemmed | Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 Inhibitors |
| title_short | Purine–Hydrazone Scaffolds as Potential Dual EGFR/HER2 Inhibitors |
| title_sort | purine hydrazone scaffolds as potential dual egfr her2 inhibitors |
| topic | cancer EGFR HER2 EGFR- and HER2-driven cancers purine/hydrazone-containing compounds lapatinib |
| url | https://www.mdpi.com/1424-8247/18/7/1051 |
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