Small Molecule Inhibitors of Programmed Cell Death Ligand 1 (PD-L1): A Patent Review (2019–2021)

ABSTRACT

Introduction

The blockade of immune checkpoints, especially the PD-1/PD-L1 pathway with therapeutic antibodies, has shown success in treating cancers in recent years. Seven monoclonal antibodies (mAbs) targeting PD-1 or PD-L1 have been approved by FDA. However, mAbs exhibit several disadvantages as compared to small molecules such as poor permeation, high manufacturing costs, immunogenicity as well as lacking oral bioavailability. Recently, small-molecule inhibitors targeting PD-L1 have been disclosed with the ability to modulate the PD-1/PD-L1 pathway.

Areas covered

The authors reviewed small molecules targeting PD-L1 that block the PD-1/PD-L1 protein–protein interaction for the treatment of various diseases.

Expert opinion

Compared with mAbs, PD-1/PD-L1 small-molecule inhibitors show several advantages such as improved tissue penetration, low immunogenicity, well-understood formulation and lower manufacturing costs. They can serve as complementary or synergistically with mAbs for immune therapy. However, at this time most of the reported inhibitors are still inferior to therapeutic antibodies in their inhibitory activities due to smaller molecular weight. Therefore, better small molecules need to be developed to improve their potencies. Moreover, although several PD-L1 small-molecule inhibitors have shown excellent preclinical results, their safety and efficacy in the clinic still awaits further validation.

KEYWORDS:

• Immune therapy
• immune checkpoints
• PD-1
• PD-L1
• small molecule inhibitors
• cancers

Article highlights

• Blocking immune checkpoints is a highly promising therapeutic method to fight various diseases, especially cancers.

• Despite PD-1/PD-L1 antibodies have gained great medical and commercial success in treating cancers, they also have various disadvantages.

• The pharmacophores of PD-L1 small-molecule inhibitors for cancer immunotherapy are summarized.

• The PD-L1 inhibitors disclosed in patents of recent 3 years are classified by different linkers they used.

This box summarizes key points contained in the article.

Declaration of interests

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 work was supported by GuangDong Basic and Applied Basic Research Foundation (No. 2020A1515110430); The authors also thank the Bioland Laboratory for financial support.