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

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.

KEYWORDS:

• Cancer immunotherapy
• co-inhibitory proteins
• small molecules
• antagonists
• anticancer drugs

Article highlights

• Therapeutic antibodies as co-inhibitory pathway antagonists have shown sustained antitumor response and patients exhibit no clinical cancer signs for many years after treatment. However, therapeutic antibodies also have various disadvantages.

• Small molecules as co-inhibitory pathway antagonists have demonstrated low immune-related serious adverse events rate and high overall clinical benefit rate in clinical trials.

• The pharmacophores of small molecules as co-inhibitory pathway antagonists for cancer immunotherapy are summarized.

• Biochemistry assays for the development of small molecules as co-inhibitory pathway antagonists are reviewed.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was partially supported by the National Cancer Institute grant R21CA184788 (to QP Dou) and the National Institutes of Health grant P30CA022453 (to the Karmanos Cancer Institute at Wayne State University), USA, as well as by projects of Shandong Province Higher Educational Science and Technology Program (J17KA101), China and Shandong Province Higher Educational Reformation Program (M2018X087), China.