Selective targeting of antiapoptotic BCL-2 proteins in cancer.

Autor: Timucin AC; Faculty of Engineering and Natural Sciences, Department of Chemical and Biological Engineering, Uskudar University, Uskudar, Istanbul, Turkey.; Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Sabanci University, Tuzla, Istanbul, Turkey., Basaga H; Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Sabanci University, Tuzla, Istanbul, Turkey., Kutuk O; Department of Medical Genetics, Adana Medical and Research Center, School of Medicine, Baskent University, Yuregir, Adana, Turkey.
Jazyk: angličtina
Zdroj: Medicinal research reviews [Med Res Rev] 2019 Jan; Vol. 39 (1), pp. 146-175. Date of Electronic Publication: 2018 May 30.
DOI: 10.1002/med.21516
Abstrakt: Circumvention of apoptotic machinery is one of the distinctive properties of carcinogenesis. Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apoptosis regulator BCL-2) proteins, determine the response of cancer cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL-2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, milestone achievements in the development of selective antiapoptotic BCL-2 proteins inhibitors for BCL-2, BCL-XL (BCL-2-like protein 1), and MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1) were summarized and their future implications were discussed. In the first section, the design and development of BCL-2/BCL-XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL-2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL-XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summarized. In the second section, MCL-1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL-1. Explicitly, studies leading to the identification of MCL-1, nonselective and selective targeting of MCL-1, and recently initiated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increasing selectivity in the design of prosurvival BCL-2 member inhibitors.
(© 2018 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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