Pyrimido[1,2-a]benzimidazoles as inhibitors of oncoproteins ubiquitin specific protease 5 and MYCN in the childhood cancer neuroblastoma.

Gadde, S; Kleynhans, A; Holien, JK; Bhadbhade, M; Nguyen, PLD; Mittra, R; Yu, TT; Carter, DR; Parker, MW; Marshall, GM; Cheung, BB; Kumar, N

Pyrimido[1,2-a]benzimidazoles as inhibitors of oncoproteins ubiquitin specific protease 5 and MYCN in the childhood cancer neuroblastoma.

Gadde, S Kleynhans, A Holien, JK Bhadbhade, M Nguyen, PLD Mittra, R Yu, TT Carter, DR Parker, MW Marshall, GM Cheung, BB Kumar, N

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Bioorg Chem, 2023, 136, pp. 106462
Issue Date:: 2023-07

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Field	Value	Language
dc.contributor.author	Gadde, S
dc.contributor.author	Kleynhans, A
dc.contributor.author	Holien, JK
dc.contributor.author	Bhadbhade, M
dc.contributor.author	Nguyen, PLD
dc.contributor.author	Mittra, R
dc.contributor.author	Yu, TT
dc.contributor.author	Carter, DR
dc.contributor.author	Parker, MW
dc.contributor.author	Marshall, GM
dc.contributor.author	Cheung, BB
dc.contributor.author	Kumar, N
dc.date.accessioned	2024-04-29T01:38:54Z
dc.date.available	2023-03-07
dc.date.available	2024-04-29T01:38:54Z
dc.date.issued	2023-07
dc.identifier.citation	Bioorg Chem, 2023, 136, pp. 106462
dc.identifier.issn	0045-2068
dc.identifier.issn	1090-2120
dc.identifier.uri	http://hdl.handle.net/10453/178438
dc.description.abstract	The MYCN oncogene and histone deacetylases (HDACs) are key driver genes in the childhood cancer, neuroblastoma. We recently described a novel pyridobenzimidazole analogue, SE486-11, which enhanced the therapeutic effectiveness of HDAC inhibitors by increasing MYCN ubiquitination through effects on the deubiquitinase, ubiquitin-specific protease 5 (USP5). Here we describe the synthesis of a novel series of pyrimido[1,2-a]benzimidazole derivatives, and an evaluation of their cytopathic effects against non-malignant and human neuroblastoma cell lines. Among the tested analogues, 4-(4-methoxyphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine (3a) was the most active compound against neuroblastoma cells (IC50 ≤ 2 µM), with low cytotoxicity (IC50 ≥ 15 µM) to normal cells. We show compound 3a bound to USP5 protein (Kd = 0.47 µM) in vitro and synergistically enhanced the efficacy of HDAC inhibitors against neuroblastoma cells. Moreover, knockdown of USP5 and MYCN in treated neuroblastoma cells showed that both USP5 and MYCN expression was necessary for the cytopathic activity of compound 3a, thus providing a clinically relevant rationale for further development of this of pyrimido[1,2-a]benzimidazole.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Bioorg Chem
dc.relation.isbasedon	10.1016/j.bioorg.2023.106462
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry
dc.subject.classification	Organic Chemistry
dc.subject.classification	3404 Medicinal and biomolecular chemistry
dc.subject.classification	3405 Organic chemistry
dc.subject.mesh	Child
dc.subject.mesh	Humans
dc.subject.mesh	Benzimidazoles
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Ubiquitin-Specific Proteases
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Benzimidazoles
dc.subject.mesh	Child
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Ubiquitin-Specific Proteases
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Child
dc.subject.mesh	Humans
dc.subject.mesh	Benzimidazoles
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Ubiquitin-Specific Proteases
dc.title	Pyrimido[1,2-a]benzimidazoles as inhibitors of oncoproteins ubiquitin specific protease 5 and MYCN in the childhood cancer neuroblastoma.
dc.type	Journal Article
utslib.citation.volume	136
utslib.location.activity	United States
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0305 Organic Chemistry
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	closed_access	*
dc.date.updated	2024-04-29T01:38:44Z
pubs.publication-status	Published
pubs.volume	136

Abstract:

The MYCN oncogene and histone deacetylases (HDACs) are key driver genes in the childhood cancer, neuroblastoma. We recently described a novel pyridobenzimidazole analogue, SE486-11, which enhanced the therapeutic effectiveness of HDAC inhibitors by increasing MYCN ubiquitination through effects on the deubiquitinase, ubiquitin-specific protease 5 (USP5). Here we describe the synthesis of a novel series of pyrimido[1,2-a]benzimidazole derivatives, and an evaluation of their cytopathic effects against non-malignant and human neuroblastoma cell lines. Among the tested analogues, 4-(4-methoxyphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine (3a) was the most active compound against neuroblastoma cells (IC50 ≤ 2 µM), with low cytotoxicity (IC50 ≥ 15 µM) to normal cells. We show compound 3a bound to USP5 protein (Kd = 0.47 µM) in vitro and synergistically enhanced the efficacy of HDAC inhibitors against neuroblastoma cells. Moreover, knockdown of USP5 and MYCN in treated neuroblastoma cells showed that both USP5 and MYCN expression was necessary for the cytopathic activity of compound 3a, thus providing a clinically relevant rationale for further development of this of pyrimido[1,2-a]benzimidazole.

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http://hdl.handle.net/10453/178438