Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives

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

doi:10.3390/ph16010043

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives

Pharmaceuticals (Basel). 2022 Dec 28;16(1):43. doi: 10.3390/ph16010043.

Authors

Ahmed Elkamhawy^{1

2}, Seohyun Son¹, Hwa Young Lee¹, Mahmoud H El-Maghrabey³, Mohamed A El Hamd^{4

5}, Saud O Alshammari⁶, Abeer A Abdelhameed⁷, Qamar A Alshammari⁸, Ahmed Abdeen⁹, Samah F Ibrahim¹⁰, Wael A Mahdi¹¹, Sultan Alshehri¹¹, Radwan Alnajjar^{12

13

14}, Won Jun Choi¹, Ahmed A Al-Karmalawy¹⁵, Kyeong Lee¹

Affiliations

¹ BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
³ Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
⁵ Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt.
⁶ Department of Plant Chemistry and Natural Products, Faculty of Pharmacy, Northern Border University, Arar 91431, Saudi Arabia.
⁷ Department of Pharmacology, Faculty of Medicine, Benha University, Benha 13518, Egypt.
⁸ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Northern Border University, Arar 91431, Saudi Arabia.
⁹ Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh 13736, Egypt.
¹⁰ Department of Clinical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
¹¹ Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
¹² Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi 16063, Libya.
¹³ PharmD, Faculty of Pharmacy, Libyan International Medical University, Benghazi 16063, Libya.
¹⁴ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
¹⁵ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.

Abstract

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 (6a-l) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound 6j 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 (6i-l) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65-99.03%) and HER2 (87.16-96.73%). Compound 6j showed nanomolar IC₅₀ values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound 6j was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound 6j 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 6j was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation.

Keywords: EGFR/HER2 dual inhibition; antiproliferative activity; kinase assay; kinase panel; lapatinib; molecular docking; nitro group containing drugs; spectroscopic characterization; synthesis.

Grants and funding

NRF-2018R1A5A2023127/National Research Foundation of Korea