Design, synthesis and antitumor study of a series of N-Cyclic sulfamoylaminoethyl substituted 1,2,5-oxadiazol-3-amines as new indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors

Shulun Chen; Wei Guo; Xiaohua Liu; Pu Sun; Yi Wang; Chunyong Ding; Linghua Meng; Ao Zhang

doi:10.1016/j.ejmech.2019.06.037

Design, synthesis and antitumor study of a series of N-Cyclic sulfamoylaminoethyl substituted 1,2,5-oxadiazol-3-amines as new indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors

Eur J Med Chem. 2019 Oct 1:179:38-55. doi: 10.1016/j.ejmech.2019.06.037. Epub 2019 Jun 17.

Authors

Shulun Chen¹, Wei Guo², Xiaohua Liu¹, Pu Sun³, Yi Wang³, Chunyong Ding¹, Linghua Meng², Ao Zhang⁴

Affiliations

¹ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
³ Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
⁴ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: aozhang@simm.ac.cn.

PMID: 31233921
DOI: 10.1016/j.ejmech.2019.06.037

Abstract

Indoleamine 2, 3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism which is an important mechanism in immune tolerance. The small molecule epacadostat is the most advanced IDO1 inhibitor, but its phase III trials as a single agent or in combinations with PD-1 antibody failed to show appreciable objective responses. To gain more insight on the antitumor efficacy of IDO1 inhibitors, we have designed a series of analogues of epacadostat by incorporating a cyclic aminosulfonamide moiety as the sidechain capping functionality. Compound 5a was found to display significant potency against recombinant hIDO1 and hIDO1 expressed HEK293 cancer cells. This compound has improved physico-chemical properties, acceptable PK parameters as well as optimal cardiac safety. Similar to epacadostat, 5a is ineffective as single agent in the CT-26 syngeneic xenograft model, however, the combination of 5a with PD-1 antibody showed both elevated tumor growth inhibition and prolonged median life span.

Keywords: Immunotherapy; Indoleamine 2,3-dioxygenase; Life span; Oxadiazole; PD-1.

MeSH terms

Amines / chemical synthesis
Amines / chemistry
Amines / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Female
HEK293 Cells
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Male
Mice
Mice, Inbred BALB C
Molecular Structure
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry
Oxadiazoles / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Amines
Antineoplastic Agents
Enzyme Inhibitors
IDO1 protein, human
Indoleamine-Pyrrole 2,3,-Dioxygenase
Oxadiazoles