Indolin-2-one derivatives as selective Aurora B kinase inhibitors targeting breast cancer.

Autor: Dokla EME; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt. Electronic address: emanelawady@pharma.asu.edu.eg., Abdel-Aziz AK; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy., Milik SN; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt; School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom., Mahmoud AH; Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland., Saadeldin MK; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy; Department of Biosciences, University of Milan, Milan 20133, Italy., McPhillie MJ; School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom., Minucci S; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy; Department of Biosciences, University of Milan, Milan 20133, Italy. Electronic address: Saverio.Minucci@ieo.it., Abouzid KAM; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2021 Dec; Vol. 117, pp. 105451. Date of Electronic Publication: 2021 Oct 24.
DOI: 10.1016/j.bioorg.2021.105451
Abstrakt: Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1). Seven derivatives, 5g, 6a, 6c-e, 7, and 8a showed preferential antiproliferative activity in NCI-60 cell line screening and out of these, carbamate 6e and cyclopropylurea 8a derivatives showed optimum activity against Aurora B (IC 50  = 16.2 and 10.5 nM respectively) and MDA-MB-468 cells (IC 50  = 32.6 ± 9.9 and 29.1 ± 7.3 nM respectively). Furthermore, 6e and 8a impaired the clonogenic potential of MDA-MB-468 cells. Mechanistic investigations indicated that 6e and 8a induced G2/M cell cycle arrest, apoptosis, and necrosis of MDA-MB-468 cells and western blot analysis of 8a effect on MDA-MB-468 cells revealed 8a's ability to reduce Aurora B and its downstream target, Histone H3 phosphorylation. 6e and 8a displayed better safety profiles than multikinase inhibitors such as sunitinib, showing no cytotoxic effects on normal rat cardiomyoblasts and murine hepatocytes. Finally, 8a demonstrated a more selective profile than 1 when screened against ten related kinases. Based on these findings, 8a represents a promising candidate for further development to target breast cancer via Aurora B selective inhibition.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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