Recent advances in small molecule based cancer immunotherapy

Abstract

Immunotherapy has been increasingly utilized for the treatment of cancer. Currently available cancer immunotherapies mainly involve the use of antibodies, which have advantages in terms of pharmacodynamics such as efficacy and specificity, however, they exhibit disadvantages in regard to the pharmacokinetics including but not limited to poor tissue and tumor penetration, very long half-life, and the lack of oral bioavailability. Also they are immunogenic and may cause undesired side effects. In addition, they are difficult and expensive to produce. In contrast to therapeutic antibodies, small molecule immuno-oncology agents generally have favorable pharmacokinetics, for example, better oral bioavailability, higher tissue and tumor penetration, reasonable half-lives etc. Furthermore, some small molecules are highly selective and efficacious with benign toxicity profiles. Therefore, small molecule immuno-oncology agents have the potential to overcome the drawbacks of therapeutic antibodies, and they can complement existing therapeutic antibodies and may also be used in combination with antibodies to achieve synergistic effects. In this article, we summarize the current advances in the field of small molecule approaches in tumor immunology which include the small molecules in clinical trials and preclinical studies, and the reported crystal structures of small molecules and their target proteins as well as the binding interactions between small molecules and the targets. The tumorigenesis mechanism of different targets (the programmed cell death 1/programmed cell death ligand 1(PD1/PD-L1), retinoic acid-related orphan receptor-gamma t (RORγt), Chemokine receptor, Stimulator of Interferon Genes (Sting), Indoleamine 2,3-dioxygenase (IDO), toll-like receptors (TLR) etc.) are also elucidated.

Keywords: Cancer immunotherapy; Crystal structures; Immuno-oncology; Inhibitors; Small molecules.