Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines

Seohyun Son; Ahmed Elkamhawy; Anam Rana Gul; Ahmed A Al-Karmalawy; Radwan Alnajjar; Ahmed Abdeen; Samah F Ibrahim; Saud O Alshammari; Qamar A Alshammari; Won Jun Choi; Tae Jung Park; Kyeong Lee

doi:10.1080/14756366.2023.2202358

Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2202358. doi: 10.1080/14756366.2023.2202358.

Authors

Seohyun Son¹, Ahmed Elkamhawy^{1

2}, Anam Rana Gul³, Ahmed A Al-Karmalawy⁴, Radwan Alnajjar^{5

6

7}, Ahmed Abdeen⁸, Samah F Ibrahim⁹, Saud O Alshammari¹⁰, Qamar A Alshammari¹¹, Won Jun Choi¹, Tae Jung Park³, Kyeong Lee¹

Affiliations

¹ College of Pharmacy, BK21 FOUR Team and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Republic of Korea.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
³ Department of Chemistry, Research Institute of Chem-Bio Diagnostic Technology, Chung-Ang University, Seoul, Republic of Korea.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
⁵ Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi, Libya.
⁶ Faculty of Pharmacy, Libyan International Medical University, Benghazi, Libya.
⁷ Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
⁸ Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt.
⁹ Department of Clinical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
¹⁰ Department of Plant Chemistry and Natural Products, Faculty of Pharmacy, Northern Border University, Arar, Saudi Arabia.
¹¹ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Northern Border University, Arar, Saudi Arabia.

Abstract

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) protein tyrosine kinases co-expressed in various cancers such as ovarian, breast, colon, and prostate subtypes. Herein, new TAK-285 derivatives (9a-h) were synthesised, characterised, and biologically evaluated as dual EGFR/HER2 inhibitors. Compound 9f exhibited IC₅₀ values of 2.3 nM over EGFR and 234 nM over HER2, which is 38-fold of staurosporine and 10-fold of TAK-285 over EGFR. Compound 9f also showed high selectivity profile when tested over a small kinase panel. Compounds 9a-h showed IC₅₀ values in the range of 1.0-7.3 nM and 0.8-2.8 nM against PC3 and 22RV1 prostate carcinoma cell lines, respectively. Cell cycle analysis, apoptotic induction, molecular docking, dynamics, and MM-GBSA studies confirmed the plausible mechanism(s) of compound 9f as a potent EGFR/HER2 dual inhibitor with an effective antiproliferative action against prostate carcinoma.

Keywords: EGFR/HER2; apoptosis; chemical synthesis; kinase panel; prostate carcinoma.

MeSH terms

Antineoplastic Agents* / pharmacology
Carcinoma*
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
ErbB Receptors
Humans
Male
Molecular Docking Simulation
Molecular Structure
Prostate
Prostatic Neoplasms*
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo(3,2-d)pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide
Antineoplastic Agents
Protein Kinase Inhibitors
EGFR protein, human
ErbB Receptors

Grants and funding

This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIT) [No. 2018R1A5A2023127] and [No. 2023R1A2C3004599]. This work is also supported by the BK21 FOUR Program, which was funded by the Ministry of Education of Korea through NRF. This research was also funded by the Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2023R127), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.