Title:A New Series of Antileukemic Agents: Design, Synthesis, <i>In Vitro</i> and <i>In Silico</i> Evaluation of Thiazole-Based ABL1 Kinase Inhibitors
VOLUME: 21 ISSUE: 9
Author(s):Ebru Zeytün, Mehlika D. Altıntop*, Belgin Sever, Ahmet Özdemir, Doha E. Ellakwa, Zeynep Ocak, Halil I. Ciftci, Masami Otsuka, Mikako Fujita* and Mohamed O. Radwan*
Affiliation:Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Department of Microbiology, Kocaeli State Hospital, Kocaeli 41300, Department of Drug Discovery, Science Farm Ltd., 1-7-30-805, Kuhonji, Chuo-ku, Kumamoto 862-0976, Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973, Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-Ku, Kumamoto 8620973
Keywords:Thiazole, ABL1 kinase, apoptosis, chronic myeloid leukemia, molecular docking, antileukemic agents.
Abstract:Background: After the approval of imatinib, more than 25 antitumor agents targeting kinases have
been approved, and several promising candidates are at various stages of clinical evaluation.
Objectives: Due to the importance of the thiazole scaffold in targeted anticancer drug discovery, the goal of this
work is to identify new thiazolyl hydrazones as potent ABL1 kinase inhibitors for the management of Chronic
Myeloid Leukemia (CML).
Methods: New thiazolyl hydrazones (2a-p) were synthesized and investigated for their cytotoxic effects on the
K562 CML cell line. Compounds 2h, 2j and 2l showed potent anticancer activity against K562 cell line. The
cytotoxic effects of these compounds on other leukemia (HL-60, MT-2 and Jurkat) and HeLa human cervical
carcinoma cell lines were also investigated. Furthermore, their cytotoxic effects on Mitogen-Activated
Peripheral Blood Mononuclear Cells (MA-PBMCs) were evaluated to determine their selectivity. Due to its
selective and potent anticancer activity, compound 2j was benchmarked for its apoptosis-inducing potential on
K562 cell line and inhibitory effects on eight different Tyrosine Kinases (TKs), including ABL1 kinase. In order
to investigate the binding mode of compound 2j into the ATP binding site of ABL1 kinase (PDB: 1IEP), a molecular
docking study was conducted using MOE 2018.01 program. The QikProp module of Schrödinger’s Molecular
modelling package was used to predict the pharmacokinetic properties of compounds 2a-p
Results: 4-(4-(Methylsulfonyl)phenyl)-2-[2-((1,3-benzodioxol-4-yl)methylene)hydrazinyl]thiazole (2j) showed
antiproliferative activity against K562 cell line with an IC50 value of 8.87±1.93 μM similar to imatinib (IC50=
6.84±1.11μM). Compound 2j was found to be more effective than imatinib on HL-60, Jurkat and MT-2 cells.
Compound 2j also showed cytotoxic activity against HeLa cell line similar to imatinib. The higher selectivity
index value of compound 2j than imatinib indicated that its antiproliferative activity was selective. Compound
2j also induced apoptosis in K562 cell line more than imatinib. Among eight TKs, compound 2j showed the
strongest inhibitory activity against ABL1 kinase enzyme (IC50= 5.37±1.17μM). According to molecular
docking studies, compound 2j exhibited high affinity to the ATP binding site of ABL1 kinase, forming
significant intermolecular interactions. On the basis of in silico studies, this compound did not violate Lipinski's
rule of five and Jorgensen's rule of three.
Conclusion: Compound 2j stands out as a potential orally bioavailable ABL1 kinase inhibitor for the treatment
of CML.
