Recent advances of human dihydroorotate dehydrogenase inhibitors for cancer therapy: Current development and future perspectives

Lele Zhang; Jifa Zhang; Jiaxing Wang; Changyu Ren; Pan Tang; Liang Ouyang; Yuxi Wang

doi:10.1016/j.ejmech.2022.114176

Recent advances of human dihydroorotate dehydrogenase inhibitors for cancer therapy: Current development and future perspectives

Eur J Med Chem. 2022 Mar 15:232:114176. doi: 10.1016/j.ejmech.2022.114176. Epub 2022 Feb 3.

Authors

Lele Zhang¹, Jifa Zhang¹, Jiaxing Wang², Changyu Ren³, Pan Tang⁴, Liang Ouyang¹, Yuxi Wang⁵

Affiliations

¹ Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
² Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States.
³ Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China.
⁴ Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
⁵ Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: yuxiwang@scu.edu.cn.

PMID: 35151222
DOI: 10.1016/j.ejmech.2022.114176

Abstract

Human dihydroorotate dehydrogenase (hDHODH) is a flavin-dependent enzyme catalyzing the fourth step of pyrimidine de novo biosynthesis. Since aberrant pyrimidine metabolism is closely related abnormal cell proliferation, hDHODH is believed to have an intimate linkage with cancers. For instance, hDHODH induces the abrogation of β-catenin degradation and cell proliferation in esophageal squamous cell carcinoma (ESCC). Thus, small molecular inhibitors targeting hDHODH has been considered as a promising strategy for cancer treatment. In recent years, in exploiting novel structural hDHODH inhibitors (hDHODHi), a candidate drug PTC299 has entered clinical trials for treating acute myelocytic leukemia (AML) and other tumors. This review discusses tumor-related research of hDHODH and highlights the structure-activity relationships of hDHODHi, providing insights into new drugs targeting hDHODH for antitumor clinical practice.

Keywords: Anticancer; Human dihydroorotate dehydrogenase (hDHODH); Small molecule inhibitors; Structure-activity relationships (SARs).

Publication types

Review

MeSH terms

Carbamates
Carbazoles
Dihydroorotate Dehydrogenase
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Esophageal Neoplasms* / drug therapy
Esophageal Squamous Cell Carcinoma* / drug therapy
Humans
Oxidoreductases Acting on CH-CH Group Donors*

Substances

Carbamates
Carbazoles
Dihydroorotate Dehydrogenase
Enzyme Inhibitors
emvododstat
Oxidoreductases Acting on CH-CH Group Donors