Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase 1 (ASK1)

Shiyan Zhang; Chaoying Huang; Xilin Lyu; Peipei Wang; Yi Zang; Zengtao Wang; Huan Wang; Jia Li; Yujun Zhao

doi:10.1016/j.ejmech.2020.112277

Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase 1 (ASK1)

Eur J Med Chem. 2020 Jun 1:195:112277. doi: 10.1016/j.ejmech.2020.112277. Epub 2020 Apr 5.

Authors

Shiyan Zhang¹, Chaoying Huang², Xilin Lyu³, Peipei Wang³, Yi Zang³, Zengtao Wang³, Huan Wang³, Jia Li⁴, Yujun Zhao⁵

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, China. Electronic address: jli@simm.ac.cn.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: yjzhao@simm.ac.cn.

PMID: 32289582
DOI: 10.1016/j.ejmech.2020.112277

Abstract

Inhibition of MAP3K kinase ASK1 has been an attractive strategy for the treatment of nonalcoholic steatohepatitis and multiple sclerosis, among others. Herein, we reported the discovery of 2-pyridinyl urea-containing compound 14l (YD57) as a potent, small-molecule inhibitor of ASK1. 14l was selective against MAP3K kinases ASK2 and TAK1 (>140-fold), while it also inhibited several cell cycle regulating kinases with IC₅₀ values in a range of 90-400 nM (<20-fold selectivity). As a consequence, 14l had stronger apoptosis induction, more potent G1 cell cycle arrest activities, and lower IC₅₀ value of cell growth inhibition than that of GS4997 in HepG2 cancer cell line. On the other hand, 14l did not inhibit ASK1 and p38 phosphorylation in intact cells. We reason that the multi-target effects of 14l likely neutralized the activities caused by inhibition of cellular ASK1. Future studies of these ASK1 inhibitors should pay close attention to their kinome selectivity profile.

Keywords: ASK1; ASK2; Apoptosis; Cell cycle arrest; Selectivity.

MeSH terms

Cell Cycle / drug effects
Drug Design*
Hep G2 Cells
Humans
Inhibitory Concentration 50
MAP Kinase Kinase Kinase 5 / antagonists & inhibitors*
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemistry*
Urea / chemistry*
Urea / pharmacology*

Substances

Protein Kinase Inhibitors
Pyridines
Urea
MAP Kinase Kinase Kinase 5
pyridine