Design, synthesis and biological evaluation of novel quinazoline derivatives as immune checkpoint inhibitors

Bioorg Med Chem Lett. 2024 Aug 1:108:129796. doi: 10.1016/j.bmcl.2024.129796. Epub 2024 May 15.

Abstract

In this work, we report 14 novel quinazoline derivatives as immune checkpoint inhibitors, IDO1 and PD-L1. The antitumor screening of synthesized compounds on ovarian cancer cells indicated that compound V-d and V-l showed the most activity with IC50 values of about 5 μM. Intriguingly, compound V-d emerges as a stand out, triggering cell death through caspase-dependent and caspase-independent manners. More importantly, V-d presents its ability to hinder tumor sphere formation and re-sensitized cisplatin-resistant A2780 cells to cisplatin treatment. These findings suggest that compound V-d emerges as a promising lead candidate for the future development of immuno anticancer agents.

Keywords: Immune check point; Indoleamine 2,3-dioxygenase 1; Ovarian cancer; Quinazoline.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor*
  • Humans
  • Immune Checkpoint Inhibitors* / chemical synthesis
  • Immune Checkpoint Inhibitors* / chemistry
  • Immune Checkpoint Inhibitors* / pharmacology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Molecular Structure
  • Quinazolines* / chemical synthesis
  • Quinazolines* / chemistry
  • Quinazolines* / pharmacology
  • Structure-Activity Relationship

Substances

  • Quinazolines
  • Immune Checkpoint Inhibitors
  • Antineoplastic Agents
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • B7-H1 Antigen
  • CD274 protein, human
  • IDO1 protein, human