Small molecules as antagonists of co-inhibitory pathways for cancer immunotherapy: a patent review (2018-2019). (1st September 2020)

• Record Type: Journal Article
• Authors: Geng, Qiaohong; Rohondia, Sagar O.; Khan, Harras J.; Jiao, Peifu; Dou, Q. Ping
• Is Part Of: Expert opinion on therapeutic patents. Volume 30:Number 9(2020)
• Page Start: 677
• Page End: 694
• Publication Date: 2020-09-01
• Subjects: Cancer immunotherapy -- co-inhibitory proteins -- small molecules -- antagonists -- anticancer drugs; Drugs -- Patents -- Periodicals; 615.10272
• DOI: 10.1080/13543776.2020.1801640
• Languages: English
• ISSNs: 1354-3776

Abstract

ABSTRACT: Introduction: Therapeutic antibodies blocking co-inhibitory pathways do not attack tumor cells directly, but instead bind to their targeted proteins and mobilize the immune system to eradicate tumors. However, only a small fraction of patients with certain cancer types can benefit from the antibodies. Additionally, antibodies have shown serious immune-related adverse events in certain patients. Small-molecule antagonists may be a complementary and potentially synergistic approach to antibodies for patients with various cancers. Areas covered: The authors review the small molecules as antagonists of co-inhibitory pathway proteins, summarize their preliminary SARs, discuss biochemistry assays used in patents for the development of small molecules as novel antagonists. Expert opinion: The disclosed pharmacophores of small molecules as co-inhibitory pathway antagonists are represented by biphenyl derivatives, biaryl derivatives, teraryl derivatives, quateraryl derivatives, and oxadiazole/thiadiazole derivatives. However, these antagonists are still inferior to therapeutic antibodies in their inhibitory activities due to relatively flat of human co-inhibitory pathways proteins. Allosteric modulators may be an alternative approach. The more safety and efficacy evaluation trials of small-molecule antagonists targeting co-inhibitory pathways should be performed to demonstrate the proof-of-principle that small-molecule antagonists can result in sustained safety and antitumor response in the near future.