Protein homodimer sequestration with small molecules: Focus on PD-L1

Biochem Pharmacol. 2020 Apr:174:113821. doi: 10.1016/j.bcp.2020.113821. Epub 2020 Jan 20.

Abstract

Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have emerged as efficient cancer biotherapeutics. In parallel, small molecules targeting PD-L1 are actively searched to offer novel therapeutic opportunities and to reduce treatment costs. Thus far, all PD-L1 small molecule inhibitors identified present the unique property to induce and to stabilize the formation of PD-L1 protein homodimers. PD-L1 itself can form heterodimers with B7-1 (CD80) but it is essentially monomeric in solution, although the homolog viral protein vOX2 is known to dimerize. Drug-induced sequestration of PD-L1 homodimers prevents binding of PD-L1 to PD-1, thus blocking the downstream signaling. We have analyzed this phenomenon of drug-induced protein dimerization to show that PD-L1 is not an isolated case. Several examples of drug-mediated protein homodimer stabilization are presented here. In particular, a similar phenomenon has been observed with small molecules, such as NSC13728 and KI-MS2-008, which stabilize Max-Max protein homodimers, to block the formation of Myc-Max heterodimers and the ensuing signalization. PD-L1, Max and ten other examples of drug-stabilized protein homodimers point to a general mechanism of protein regulation by small molecules. Nevertheless, the extent and functions of drug-induced PD-L1 homodimers await validation in vivo.

Keywords: Cancer; Immunotherapy; Max; PD-L1; Protein dimer.

Publication types

  • Review

MeSH terms

  • Acetamides / pharmacology
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • B7-H1 Antigen / chemistry*
  • B7-H1 Antigen / metabolism*
  • Humans
  • Protein Multimerization / drug effects*
  • Protein Multimerization / physiology
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Pyridines / pharmacology

Substances

  • Acetamides
  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • BMS202
  • CD274 protein, human
  • Pyridines