Advances in Small Molecule Drugs Targeting PD-1/PD-L1

PD-1/L1 antibodies can be said to be the current hot direction in the development of targeted cancer drugs. However, monoclonal antibodies have many inherent drawbacks, including poor oral bioavailability, prolonged tissue retention time and half-life, poor membrane permeability, transportation and storage, etc. In addition, the high cost of antibody drugs is also a non-negligible problem. Therefore, more and more researchers are exploring small molecule drugs as PD-1/L1 inhibitors to circumvent the disadvantages of therapeutic antibodies.

Design of Small Molecules Targeting PD-1/PD-L1

PD-1/PD-L1 receptor-ligand interactions are classical examples of protein-protein interactions (PPIs). Designing inhibitors for these interactions is extremely challenging. This is mainly due to

  • The large contact area of the interaction.
  • Absence of deep and well-defined binding pockets suitable for high affinity binding of ligands.
  • Lack of endogenous small molecule ligands as reference standards.

Progress in analyzing the crystal structures of PD-1/PD-L1 and PD-1/PD-L2 complexes has led to the identification of several potential hotspot regions, which are considered ideal for binding PD-L1 using conventional small molecules. Currently, there are two main distinct classes of small-molecule inhibitors targeting PD-L1.

  • Compounds based on the biphenyl scaffold
  • Amino acid-inspired small molecules mimicking the receptor-ligand interface identified in functional assays

Biphenyl Derivatives and Peptides

Scientists have developed a series of biphenyl core-based small molecule inhibitors based on the mechanism of PD-1/PD-L1 interaction. Among the new modified biphenyl scaffolds, compounds with C2 symmetry or pseudo-symmetry containing polar groups have gained much attention over asymmetric structures.

Checkpoint proteins are membrane proteins, most of which are derived from the B7 family. Most members of the B7 family and their ligands belong to the immunoglobulin superfamily (IgSF). The receptor-ligand interactions of IgSF proteins are mediated through loops, chains, or loops and chains. Peptide design based on these interaction interfaces is a well-established strategy for PPI inhibitor design.

Mechanism of Action of Small Molecules Targeting PD-1/PD-L1

Although most molecules are designed from the ability to bind to one of the PD-1/PD-L1 complexes and block the interaction, emerging research suggests that some compounds antagonize PD-1 signaling with additional complexity, such as:

  • Induction of PD-L1 dimerization and inhibition of PD-1/PD-L1 interaction
  • Blocking PD-L1 export from the endoplasmic reticulum to the Golgi apparatus
  • Induce PD-L1 dimerization and internalization
  • Bind to PD-L1 without interfering with PD1/PD-L1 complex formation

Based on these characteristics, strategies to develop small molecule inhibitors of immune checkpoints have attracted wide interest in the field of cancer immunotherapy. At Creative Biolabs, we are at the forefront of these advances, working to immune checkpoint targeted small molecule development. Please do not hesitate to contact us with your particular needs.

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