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

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.

Feasibility of Repurposing Clioquinol for Cancer Therapy.

BACKGROUND: Cancer is a prevalent disease in the world and is becoming more widespread as time goes on. Advanced and more effective chemotherapeutics need to be developed for the treatment of cancer to keep up with this prevalence. Repurposing drugs is an alternative to discover new chemotherapeutics. Clioquinol is currently being studied for reposition as an anti-cancer drug. OBJECTIVE: This study aimed to summarize the anti-cancer effects of clioquinol and its derivatives through a detailed literature and patent review and to review their potential re-uses in cancer treatment. METHODS: Research articles were collected through a PubMed database search using the keywords "Clioquinol" and "Cancer." The keywords "Clioquinol Derivatives" and "Clioquinol Analogues" were also used on a PubMed database search to gather research articles on clioquinol derivatives. Patents were gathered through a Google Patents database search using the keywords "Clioquinol" and "Cancer." RESULTS: Clioquinol acts as a copper and zinc ionophore, a proteasome inhibitor, an anti-angiogenesis agent, and is an inhibitor of key signal transduction pathways responsible for its growth-inhibitory activity and cytotoxicity in cancer cells preclinically. A clinical trial conducted by Schimmer et al., resulted in poor outcomes that prompted studies on alternative clioquinol-based applications, such as new combinations, new delivery methods, or new clioquinol-derived analogues. In addition, numerous patents claim alternative uses of clioquinol for cancer therapy. CONCLUSION: Clioquinol exhibits anti-cancer activities in many cancer types, preclinically. Low therapeutic efficacy in a clinical trial has prompted new studies that aim to discover more effective clioquinol- based cancer therapies.