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

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.
Seohyun Son 1,  Ahmed Elkamhawy 1 2,  Anam Rana Gul 3,  Ahmed A Al-Karmalawy 4,  Radwan Alnajjar 5 6 7,  Ahmed Abdeen 8,  Samah F Ibrahim 9,  Saud O Alshammari 10,  Qamar A Alshammari 11,  Won Jun Choi 1,  Tae Jung Park 3,  Kyeong Lee 1
Affiliations

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.
PMID: 37096560 DOI: 10.1080/14756366.2023.2202358
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.

Figures
Products