The expanding role for small molecules in immuno-oncology

• Published in: Nature reviews. Drug discovery Vol. 21; no. 11; pp. 821 - 840
• Main Authors: Offringa, Rienk, Kötzner, Lisa, Huck, Bayard, Urbahns, Klaus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2022; Nature Publishing Group
• Subjects: 631/154; 631/67/1059/2325; 631/67/580; 692/308/153; Antibodies; Antigens; Apoptosis; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Cancer therapies; Cell cycle; Chemokines; Chemotherapy; Clinical trials; Cytokines; Drug development; Drugs; FDA approval; Ligands; Lymphocytes; Medical research; Medicinal Chemistry; Melanoma; Metastasis; Molecular Medicine; Oncology; Pharmacology/Toxicology; Proteins; R&D; Research & development; Review Article; Tumors
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/s41573-022-00538-9

The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed against additional checkpoint proteins, there is an increasing interest in small-molecule immuno-oncology drugs that address intracellular pathways, some of which have recently entered clinical trials. In parallel, small molecules that target pro-tumorigenic pathways in cancer cells and the tumour microenvironment have been found to have immunostimulatory effects that synergize with the action of ICI antibodies, leading to the approval of an increasing number of regimens that combine such drugs. Combinations with small molecules targeting cancer metabolism, cytokine/chemokine and innate immune pathways, and T cell checkpoints are now under investigation. This Review discusses the recent milestones and hurdles encountered in this area of drug development, as well as our views on the best path forward. This Review provides an update on the application of small-molecule drugs in immuno-oncology, discussing current development of small molecules designed to stimulate the antitumour immune response directly and indirectly, and the rapidly increasing efforts towards the discovery of small molecules that target T cell checkpoints.