2. Academic Validation
  3. Synthesis and structure-activity relationship studies of LLY-507 analogues as SMYD2 inhibitors

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

  • Bioorg Med Chem Lett. 2020 Nov 15;30(22):127598. doi: 10.1016/j.bmcl.2020.127598.
Bin Zhang 1,  Liping Liao 2,  Fan Wu 1,  Fengcai Zhang 2,  Zhongya Sun 2,  Haijun Chen 3,  Cheng Luo 4
Affiliations

Affiliations

  • 1 Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
  • 3 Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China. Electronic address: chenhaij@gmail.com.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China. Electronic address: cluo@simm.ac.cn.
PMID: 33011288 DOI: 10.1016/j.bmcl.2020.127598
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.

Keywords

SMYD2 inhibitors; Structure-activity relationships; Thermal shift assay.

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