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Design, Synthesis, and Protein Methyltransferase Activity of a Unique Set of Constrained Amine Containing Compounds

Design, Synthesis, and Protein Methyltransferase Activity of a Unique Set of Constrained Amine Containing Compounds

Hao Zhou, Xin Che, Guochen Bao, Na Wang, Li Peng, Kimberly D Barnash, Stephen V Frye, Lindsey I James, Xu Bai

Bioorg Med Chem Lett. 2016 Sep 15;26(18):4436-4440.

PMID: 27528434

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1184136104	UNC926		1184136-10-4	Price

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