Synthesis and structure–activity relationship studies of LLY-507 analogues as SMYD2 inhibitors - Details

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Abstract：

SET　and　MYND　domain-containing　protein　2　(SMYD2),　a　lysine　methyltransferase,　is　reported　to　catalyze　the　methylation　of　lysine　residues　on　histone　and　non-histone　proteins.　As　a　potential　target　for　cancer　therapy,　there　are　several　SMYD2　inhibitors　are　reported,　LLY-507　as　a　cell-active　inhibitor　exhibits　submicromolar　potency　against　SMYD2　in　several　cancer　cell　lines.　To　know　which　structural　fragment　of　LLY-507　is　suitable　for　chemical　modification,　three　sites　are　chosen　for　structure–activity　relationship　studies　(SARs).　Among　our　focused　library,　compounds　43　and　44　with　amide　link　on　site　C　showed　reasonably　improved　potency　indicating　that　modification　on　this　fragment　is　more　flexible　and　introduction　of　electrophilic　warheads　in　this　position　might　provide　lysine-targeting　covalent　inhibitors　for　SMYD2.　©　2020　Elsevier　Ltd

Keyword：

SMYD2 inhibitors; Structure-activity relationships; Thermal shift assay

Community：

[ 1 ] [Zhang, B.]Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
[ 2 ] [Liao, L.]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
[ 3 ] [Liao, L.]University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
[ 4 ] [Wu, F.]Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
[ 5 ] [Zhang, F.]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
[ 6 ] [Zhang, F.]University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
[ 7 ] [Sun, Z.]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
[ 8 ] [Sun, Z.]University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
[ 9 ] [Chen, H.]Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
[ 10 ] [Luo, C.]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China
[ 11 ] [Luo, C.]University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China

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Bioorganic and Medicinal Chemistry Letters

ISSN： 0960-894X

Year： 2020

Issue： 22

Volume： 30

2 . 8 2 3

JCR@2020

2 . 5 0 0

JCR@2023

ESI HC Threshold：160

JCR Journal Grade：2

CAS Journal Grade：3

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ESI Highly Cited Papers on the List： 0 Unfold All

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