Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds.

Zhou, H; Che, X; Bao, G; Wang, N; Peng, L; Barnash, KD; Frye, SV; James, LI; Bai, X

Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds.

Zhou, H Che, X Bao, G

Wang, N Peng, L Barnash, KD Frye, SV James, LI Bai, X

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Publisher:: PERGAMON-ELSEVIER SCIENCE LTD
Publication Type:: Journal Article
Citation:: Bioorg Med Chem Lett, 2016, 26, (18), pp. 4436-4440
Issue Date:: 2016-09-15

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Field	Value	Language
dc.contributor.author	Zhou, H
dc.contributor.author	Che, X
dc.contributor.author	Bao, G https://orcid.org/0000-0001-5103-5009
dc.contributor.author	Wang, N
dc.contributor.author	Peng, L
dc.contributor.author	Barnash, KD
dc.contributor.author	Frye, SV
dc.contributor.author	James, LI
dc.contributor.author	Bai, X
dc.date.accessioned	2022-08-15T19:37:00Z
dc.date.available	2016-08-02
dc.date.available	2022-08-15T19:37:00Z
dc.date.issued	2016-09-15
dc.identifier.citation	Bioorg Med Chem Lett, 2016, 26, (18), pp. 4436-4440
dc.identifier.issn	0960-894X
dc.identifier.issn	1464-3405
dc.identifier.uri	http://hdl.handle.net/10453/160235
dc.description.abstract	Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by the known multicyclic ligands, UNC669 and UNC926, which are the first reported small molecule ligands for a methyl-lysine binding domain. We hypothesized that reducing the conformational flexibility of the key amine moiety of UNC669 would result in a unique set of ligands. Twenty-five novel compounds containing a fused bi- or tricyclic amine or a spirocyclic amine were designed and synthesized. To gauge the potential of these amine-containing compounds to interact with Kme regulatory proteins, the compounds were screened against a panel of 24 protein methyltransferases. Compound 13 was discovered as a novel scaffold that interacts with SETD8 and could serve as a starting point for the future development of PKMT inhibitors.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	PERGAMON-ELSEVIER SCIENCE LTD
dc.relation.ispartof	Bioorg Med Chem Lett
dc.relation.isbasedon	10.1016/j.bmcl.2016.08.004
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Medicinal & Biomolecular Chemistry
dc.subject.mesh	Amines
dc.subject.mesh	Drug Design
dc.subject.mesh	Methyltransferases
dc.subject.mesh	Amines
dc.subject.mesh	Methyltransferases
dc.subject.mesh	Drug Design
dc.title	Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds.
dc.type	Journal Article
utslib.citation.volume	26
utslib.location.activity	England
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0305 Organic Chemistry
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access	*
dc.date.updated	2022-08-15T19:36:59Z
pubs.issue	18
pubs.publication-status	Published
pubs.volume	26
utslib.citation.issue	18

Abstract:

Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by the known multicyclic ligands, UNC669 and UNC926, which are the first reported small molecule ligands for a methyl-lysine binding domain. We hypothesized that reducing the conformational flexibility of the key amine moiety of UNC669 would result in a unique set of ligands. Twenty-five novel compounds containing a fused bi- or tricyclic amine or a spirocyclic amine were designed and synthesized. To gauge the potential of these amine-containing compounds to interact with Kme regulatory proteins, the compounds were screened against a panel of 24 protein methyltransferases. Compound 13 was discovered as a novel scaffold that interacts with SETD8 and could serve as a starting point for the future development of PKMT inhibitors.

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http://hdl.handle.net/10453/160235