Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives
Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/1/43 |
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| author | Ahmed Elkamhawy Seohyun Son Hwa Young Lee Mahmoud H. El-Maghrabey Mohamed A. El Hamd Saud O. Alshammari Abeer A. Abdelhameed Qamar A. Alshammari Ahmed Abdeen Samah F. Ibrahim Wael A. Mahdi Sultan Alshehri Radwan Alnajjar Won Jun Choi Ahmed A. Al-Karmalawy Kyeong Lee |
| author_facet | Ahmed Elkamhawy Seohyun Son Hwa Young Lee Mahmoud H. El-Maghrabey Mohamed A. El Hamd Saud O. Alshammari Abeer A. Abdelhameed Qamar A. Alshammari Ahmed Abdeen Samah F. Ibrahim Wael A. Mahdi Sultan Alshehri Radwan Alnajjar Won Jun Choi Ahmed A. Al-Karmalawy Kyeong Lee |
| author_sort | Ahmed Elkamhawy |
| collection | DOAJ |
| description | Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many patients do not respond to it or develop resistance for a variety of reasons that are still unclear. As a result, new approaches and inhibitory small molecules are still needed for EGFR/HER2 inhibition. Herein, novel lapatinib derivatives possessing 4-anilinoquinazoline and imidazole scaffolds (<b>6a</b>–<b>l</b>) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound <b>6j</b> has a high affinity for the ATP-binding regions of EGFR and HER2. All of the designed candidates were predicted to not penetrate the BBB, raising the expectation for the absence of CNS side effects. At 10 µM, derivatives possessing 3-chloro-4-(pyridin-2-ylmethoxy)aniline moiety (<b>6i</b>–<b>l</b>) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65–99.03%) and HER2 (87.16–96.73%). Compound <b>6j</b> showed nanomolar IC<sub>50</sub> values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound <b>6j</b> was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound <b>6j</b> showed poor to weak inhibitory activity over CDK2/cyclin A, c-MET, FGFR1, KDR/VEGFR2, and P38a/MAPK14, respectively. Structure–activity relationship (SAR) that were obtained with different substitutions were justified. Additionally, molecular docking and molecular dynamics studies revealed insights into the binding mode of the target compounds. Thus, compound <b>6j</b> was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation. |
| first_indexed | 2024-03-09T11:29:21Z |
| format | Article |
| id | doaj.art-373bf5a6def6412094a0e8a1752921b6 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T11:29:21Z |
| publishDate | 2022-12-01 |
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| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-373bf5a6def6412094a0e8a1752921b62023-11-30T23:54:58ZengMDPI AGPharmaceuticals1424-82472022-12-011614310.3390/ph16010043Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib DerivativesAhmed Elkamhawy0Seohyun Son1Hwa Young Lee2Mahmoud H. El-Maghrabey3Mohamed A. El Hamd4Saud O. Alshammari5Abeer A. Abdelhameed6Qamar A. Alshammari7Ahmed Abdeen8Samah F. Ibrahim9Wael A. Mahdi10Sultan Alshehri11Radwan Alnajjar12Won Jun Choi13Ahmed A. Al-Karmalawy14Kyeong Lee15BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaBK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaBK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaDepartment of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, EgyptDepartment of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi ArabiaDepartment of Plant Chemistry and Natural Products, Faculty of Pharmacy, Northern Border University, Arar 91431, Saudi ArabiaDepartment of Pharmacology, Faculty of Medicine, Benha University, Benha 13518, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Northern Border University, Arar 91431, Saudi ArabiaDepartment of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh 13736, EgyptDepartment of Clinical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Chemistry, Faculty of Science, University of Benghazi, Benghazi 16063, LibyaBK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaPharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, EgyptBK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaCo-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many patients do not respond to it or develop resistance for a variety of reasons that are still unclear. As a result, new approaches and inhibitory small molecules are still needed for EGFR/HER2 inhibition. Herein, novel lapatinib derivatives possessing 4-anilinoquinazoline and imidazole scaffolds (<b>6a</b>–<b>l</b>) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound <b>6j</b> has a high affinity for the ATP-binding regions of EGFR and HER2. All of the designed candidates were predicted to not penetrate the BBB, raising the expectation for the absence of CNS side effects. At 10 µM, derivatives possessing 3-chloro-4-(pyridin-2-ylmethoxy)aniline moiety (<b>6i</b>–<b>l</b>) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65–99.03%) and HER2 (87.16–96.73%). Compound <b>6j</b> showed nanomolar IC<sub>50</sub> values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound <b>6j</b> was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound <b>6j</b> showed poor to weak inhibitory activity over CDK2/cyclin A, c-MET, FGFR1, KDR/VEGFR2, and P38a/MAPK14, respectively. Structure–activity relationship (SAR) that were obtained with different substitutions were justified. Additionally, molecular docking and molecular dynamics studies revealed insights into the binding mode of the target compounds. Thus, compound <b>6j</b> was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation.https://www.mdpi.com/1424-8247/16/1/43nitro group containing drugsantiproliferative activityEGFR/HER2 dual inhibitionsynthesiskinase panellapatinib |
| spellingShingle | Ahmed Elkamhawy Seohyun Son Hwa Young Lee Mahmoud H. El-Maghrabey Mohamed A. El Hamd Saud O. Alshammari Abeer A. Abdelhameed Qamar A. Alshammari Ahmed Abdeen Samah F. Ibrahim Wael A. Mahdi Sultan Alshehri Radwan Alnajjar Won Jun Choi Ahmed A. Al-Karmalawy Kyeong Lee Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives Pharmaceuticals nitro group containing drugs antiproliferative activity EGFR/HER2 dual inhibition synthesis kinase panel lapatinib |
| title | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives |
| title_full | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives |
| title_fullStr | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives |
| title_full_unstemmed | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives |
| title_short | Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives |
| title_sort | design synthesis biological evaluation and molecular dynamics studies of novel lapatinib derivatives |
| topic | nitro group containing drugs antiproliferative activity EGFR/HER2 dual inhibition synthesis kinase panel lapatinib |
| url | https://www.mdpi.com/1424-8247/16/1/43 |
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