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Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells

Juan Bautista Menendez-Gonzalez, Kathryn E. Strange, Marcella Bassetto, Andrea Brancale, Neil P. Rodrigues, Salvatore Ferla Orcid Logo

Frontiers in Drug Discovery, Volume: 2

Swansea University Authors: Marcella Bassetto, Salvatore Ferla Orcid Logo

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DOI (Published version): 10.3389/fddsv.2022.1013229

Abstract

Despite major therapeutic advances leading to improved patient outcomes for other haematological malignancies, development of new therapeutics to improve prognosis for acute myeloid leukemia (AML) patients remains an area of unmet clinical need. Overexpression of GATA2, a member of the GATA family o...

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Published in: Frontiers in Drug Discovery
ISSN: 2674-0338
Published: Frontiers Media SA 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa61795
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Overexpression of GATA2, a member of the GATA family of zinc finger transcription factors, has been implicated in AML. In settings where GATA2 is overexpressed in human AML cells, K7174, a proteasome inhibitor that inhibits GATA2, induces apoptosis and enhances the killing activity of AML chemotherapeutics in vitro yet targeting the proteasome has been associated with high toxicity in the clinic. Using an in silico approach, we embarked on a screen to identify specific GATA2 inhibitors that will target AML cells independently of the proteasome. A shape-based virtual screening of an in-house library of small molecules was performed using a low-energy conformation of K7174. The virtual hit compounds were subsequently filtered according to their potential selectivity for GATA2 over the proteasome. From 15 selected compounds evaluated for their ability to kill AML cells in vitro, one compound, an asymmetrical substituted piperazine with Hepatitis C antiviral activity, exhibited superior ability to induce apoptosis and reduce cell cycling in AML cells without proteasome inhibition. This compound was also able to promote cell death of the relapse propagating leukemic stem cell (LSC) compartment while sparing Gata2 knockout LSCs, crucially demonstrating specificity to inhibit GATA2. 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spelling 2022-11-28T16:02:11.9764926 v2 61795 2022-11-07 Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false 2022-11-07 FGSEN Despite major therapeutic advances leading to improved patient outcomes for other haematological malignancies, development of new therapeutics to improve prognosis for acute myeloid leukemia (AML) patients remains an area of unmet clinical need. Overexpression of GATA2, a member of the GATA family of zinc finger transcription factors, has been implicated in AML. In settings where GATA2 is overexpressed in human AML cells, K7174, a proteasome inhibitor that inhibits GATA2, induces apoptosis and enhances the killing activity of AML chemotherapeutics in vitro yet targeting the proteasome has been associated with high toxicity in the clinic. Using an in silico approach, we embarked on a screen to identify specific GATA2 inhibitors that will target AML cells independently of the proteasome. A shape-based virtual screening of an in-house library of small molecules was performed using a low-energy conformation of K7174. The virtual hit compounds were subsequently filtered according to their potential selectivity for GATA2 over the proteasome. From 15 selected compounds evaluated for their ability to kill AML cells in vitro, one compound, an asymmetrical substituted piperazine with Hepatitis C antiviral activity, exhibited superior ability to induce apoptosis and reduce cell cycling in AML cells without proteasome inhibition. This compound was also able to promote cell death of the relapse propagating leukemic stem cell (LSC) compartment while sparing Gata2 knockout LSCs, crucially demonstrating specificity to inhibit GATA2. We have identified a GATA2 specific inhibitor with promising capability to target AML cells in vitro, including LSCs that underpin poor prognosis in AML. Journal Article Frontiers in Drug Discovery 2 Frontiers Media SA 2674-0338 GATA2, acute myeloid leukaemia, virtual shape based screen, in silico, proteasome inhibitor 5 10 2022 2022-10-05 10.3389/fddsv.2022.1013229 COLLEGE NANME Science and Engineering - Faculty COLLEGE CODE FGSEN Swansea University This project was supported by Life Sciences Research Network, Wales (to JM-G and NR) and the Leukemia Cancer Society (to NR). SF was supported by the Ser Cymru II program which part-funded by Swansea University and the European Regional Development Fund through the Welsh Government. 2022-11-28T16:02:11.9764926 2022-11-07T13:04:04.8886774 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Juan Bautista Menendez-Gonzalez 1 Kathryn E. Strange 2 Marcella Bassetto 3 Andrea Brancale 4 Neil P. Rodrigues 5 Salvatore Ferla 0000-0002-5918-9237 6 61795__25795__af769123281f4cd4a938e94dd8204c53.pdf 61795.pdf 2022-11-16T11:44:38.8390507 Output 1469727 application/pdf Version of Record true © 2022 Menendez-Gonzalez, Strange, Bassetto, Brancale, Rodrigues and Ferla. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) true eng https://creativecommons.org/licenses/by/4.0/
title Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells
spellingShingle Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells
Marcella Bassetto
Salvatore Ferla
title_short Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells
title_full Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells
title_fullStr Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells
title_full_unstemmed Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells
title_sort Ligand-based discovery of a novel GATA2 inhibitor targeting acute myeloid leukemia cells
author_id_str_mv b97beeed16f8e0524551233ade909565
d4c62248f510e3b221916989a7bbe6a6
author_id_fullname_str_mv b97beeed16f8e0524551233ade909565_***_Marcella Bassetto
d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
author Marcella Bassetto
Salvatore Ferla
author2 Juan Bautista Menendez-Gonzalez
Kathryn E. Strange
Marcella Bassetto
Andrea Brancale
Neil P. Rodrigues
Salvatore Ferla
format Journal article
container_title Frontiers in Drug Discovery
container_volume 2
publishDate 2022
institution Swansea University
issn 2674-0338
doi_str_mv 10.3389/fddsv.2022.1013229
publisher Frontiers Media SA
college_str Faculty of Science and Engineering
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hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 1
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description Despite major therapeutic advances leading to improved patient outcomes for other haematological malignancies, development of new therapeutics to improve prognosis for acute myeloid leukemia (AML) patients remains an area of unmet clinical need. Overexpression of GATA2, a member of the GATA family of zinc finger transcription factors, has been implicated in AML. In settings where GATA2 is overexpressed in human AML cells, K7174, a proteasome inhibitor that inhibits GATA2, induces apoptosis and enhances the killing activity of AML chemotherapeutics in vitro yet targeting the proteasome has been associated with high toxicity in the clinic. Using an in silico approach, we embarked on a screen to identify specific GATA2 inhibitors that will target AML cells independently of the proteasome. A shape-based virtual screening of an in-house library of small molecules was performed using a low-energy conformation of K7174. The virtual hit compounds were subsequently filtered according to their potential selectivity for GATA2 over the proteasome. From 15 selected compounds evaluated for their ability to kill AML cells in vitro, one compound, an asymmetrical substituted piperazine with Hepatitis C antiviral activity, exhibited superior ability to induce apoptosis and reduce cell cycling in AML cells without proteasome inhibition. This compound was also able to promote cell death of the relapse propagating leukemic stem cell (LSC) compartment while sparing Gata2 knockout LSCs, crucially demonstrating specificity to inhibit GATA2. We have identified a GATA2 specific inhibitor with promising capability to target AML cells in vitro, including LSCs that underpin poor prognosis in AML.
published_date 2022-10-05T04:20:53Z
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