Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors

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http://hdl.handle.net/10138/335081

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Selberg , S , Seli , N , Kankuri , E & Karelson , M 2021 , ' Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors ' , ACS Omega , vol. 6 , no. 20 , pp. 13310-13320 . https://doi.org/10.1021/acsomega.1c01289

Title: Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors
Author: Selberg, S; Seli, N; Kankuri, E; Karelson, M
Contributor organization: Doctoral Programme in Drug Research
Doctoral Programme in Biomedicine
Esko Markus Kankuri / Principal Investigator
Medicum
Department of Pharmacology
Date: 2021-05-25
Language: eng
Number of pages: 11
Belongs to series: ACS Omega
ISSN: 2470-1343
DOI: https://doi.org/10.1021/acsomega.1c01289
URI: http://hdl.handle.net/10138/335081
Abstract: The RNA 6-N-methyladenosine (m6A) demethylase ALKBH5 has been shown to be oncogenic in several cancer types, including leukemia and glioblastoma. We present here the target-tailored development and first evaluation of the antiproliferative effects of new ALKBH5 inhibitors. Two compounds, 2-[(1-hydroxy-2-oxo-2-phenylethyl)sulfanyl]acetic acid (3) and 4-{[(furan-2-yl)methyl]amino}-1,2-diazinane-3,6-dione (6), with IC50 values of 0.84 mu M and 1.79 mu M, respectively, were identified in high-throughput virtual screening of the library of 144 000 preselected compounds and subsequent verification of hits in an m6A antibody-based enzyme-linked immunosorbent assay (ELISA) enzyme inhibition assay. The effect of these compounds on the proliferation of selected target cancer cell lines was then measured. In the case of three leukemia cell lines (HL-60, CCRF-CEM, and K562) the cell proliferation was suppressed at low micromolar concentrations of inhibitors, with IC50 ranging from 1.38 to 16.5 mu M. However, the effect was low or negligible in the case of another leukemia cell line, Jurkat, and the glioblastoma cell line A-172. These results demonstrate the potential of ALKBH5 inhibition as a cancer-cell-type-selective antiproliferative strategy.
Subject: STRUCTURAL BASIS
M(6)A RNA
EXPRESSION
PROLIFERATION
CELLS
TUMORIGENICITY
PROMOTE
BINDING
PROTEIN
REVEAL
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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