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

Bin Zhang; Liping Liao; Fan Wu; Fengcai Zhang; Zhongya Sun; Haijun Chen; Cheng Luo

doi:10.1016/j.bmcl.2020.127598

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. Epub 2020 Oct 2.

Authors

Bin Zhang¹, Liping Liao², Fan Wu¹, Fengcai Zhang², Zhongya Sun², Haijun Chen³, Cheng Luo⁴

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
Histone-Lysine N-Methyltransferase / metabolism
Humans
Molecular Structure
Pyrrolidines / chemical synthesis
Pyrrolidines / chemistry
Pyrrolidines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzamides
Enzyme Inhibitors
LLY-507
Pyrrolidines
Histone-Lysine N-Methyltransferase
SMYD2 protein, human