Type IIA - Type IIB protein tyrosine kinase inhibitors hybridization as an efficient approach for potent multikinase inhibitor development: Design, synthesis, anti-proliferative activity, multikinase inhibitory activity and molecular modeling of novel indolinone-based ureides and amides

Wagdy M Eldehna; Ahmed M El Kerdawy; Ghada H Al-Ansary; Sara T Al-Rashood; Mamdouh M Ali; Abeer E Mahmoud

doi:10.1016/j.ejmech.2018.11.061

Type IIA - Type IIB protein tyrosine kinase inhibitors hybridization as an efficient approach for potent multikinase inhibitor development: Design, synthesis, anti-proliferative activity, multikinase inhibitory activity and molecular modeling of novel indolinone-based ureides and amides

Eur J Med Chem. 2019 Feb 1:163:37-53. doi: 10.1016/j.ejmech.2018.11.061. Epub 2018 Nov 24.

Authors

Wagdy M Eldehna¹, Ahmed M El Kerdawy², Ghada H Al-Ansary³, Sara T Al-Rashood⁴, Mamdouh M Ali⁵, Abeer E Mahmoud⁵

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt. Electronic address: wagdy2000@gmail.com.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, P.O. Box 11566, Egypt; Department of Pharmaceutical Chemistry, Pharmacy Program, Batterejee Medical College, Jeddah, P.O. Box 6231, Saudi Arabia.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
⁵ Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Dokki, 12622, Giza, Egypt.

PMID: 30503942
DOI: 10.1016/j.ejmech.2018.11.061

Abstract

Pursuing on our efforts regarding development of novel multikinase inhibitors, herein we report the design and synthesis of novel 2-indolinone-based ureides 6a-u and amides 10a-j. In this work we adopt a hybridization strategy between type IIA PTK inhibitor (sorafenib) and type IIB PTK inhibitors (sunitinib and nintedanib). This was implemented via linking the indolinone core, in both sunitinib and nintedanib, which is well-fitted in the hinge region in the kinase domain front cleft and the biaryl urea extension, in sorafenib, which is accommodated in the gate area and the hydrophobic back pocket. Molecular docking of the designed hybrid compounds in VEGFR-2 and FGFR-1 active sites revealed, as planned, their ability to establish the binding interactions achieved by both original type IIA and type IIB inhibitors. The designed compounds were evaluated for their multikinase inhibitory activity towards VEGFR-2, PDGFR-b and FGFR-1 and anti-proliferative activity towards HepG2, MCF-7, A549 and A498 cancer cell lines. The ureido analogue 6u emerged as the most potent multikinase inhibitor in the ureido series with VEGFR-2, FGFR-1 and PDGFR-b IC₅₀ of 0.18, 0.23 and 0.10 μM, respectively. Whereas, the amido congener 10j emerged as the most potent multikinase inhibitor in the amide series with VEGFR-2, FGFR-1 and PDGFR-b IC₅₀ of 0.28, 0.46 and 0.09 μM, respectively. While, indolinone 6u was the most potent derivative towards HepG2 cells (IC₅₀ = 2.67 ± 0.14 μM), 6r stood out as the most potent indolinone against A498 cells (IC₅₀ = 0.78 ± 0.02 μM). Additionally, the target indolinones displayed non-significant cytotoxic impact towards human normal melanocyte (HFB4). ADME prediction study of the designed compounds showed that they are not only with promising multikinase inhibitory activity but also with favorable pharmacokinetic and drug-likeness properties. Compounds 6r and 10j are revealed to be the best compounds in terms of multikinase activity and pharmacokinetics.

Keywords: FGFR-1 and PDGFR-b; Indolinone; Molecular modeling; Multikinase inhibitor; Synthesis; VEGFR-2.

MeSH terms

Amides / chemical synthesis*
Amides / pharmacology
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Humans
Indoles / pharmacology
Models, Molecular
Oxindoles / chemical synthesis
Oxindoles / pharmacology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
Sorafenib / pharmacology
Structure-Activity Relationship
Sunitinib / pharmacology
TYK2 Kinase / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors

Substances

Amides
Antineoplastic Agents
Indoles
Oxindoles
Protein Kinase Inhibitors
Sorafenib
tyrosine protein kinase IIB
FGFR1 protein, human
KDR protein, human
Protein-Tyrosine Kinases
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Platelet-Derived Growth Factor beta
Vascular Endothelial Growth Factor Receptor-2
TYK2 Kinase
TYK2 protein, human
nintedanib
Sunitinib