Therapeutic Targeting of PD-1/PD-L1 blockade by Novel Small-molecule Inhibitors

Interactions between programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) lead to the evasion of cancer cells from an efficient immune response. The inhibition of PD-L1/PD-1 has prevented or reversed exhausted T cells, thus enhancing antitumor T-cell responses. In fact, immune checkpoint blockade targeting the PD-1 axis has become one of the most effective therapies for diverse cancers.

While tremendous clinical benefits are observed in patients who respond to monoclonal antibodies (mAb), the lack of understanding of the mechanistic basis regulating this immune checkpoint pathway results in low response rates (~25%), absence of long-term remission, and severe immune-related adverse events (IRAEs). Besides, mAb are very expensive to produce, which in addition to their required intravenous administration, results in high-cost treatment regimens which are financially inaccessible to many. These limitations and others preclude that the full potential of the immune checkpoint blockade has yet to be fulfilled.

Our solution unveils the promising application of small molecules as a new class of PD-L1/PD-1 signaling pathway regulators with the following advantages compared to mAbs:
• Offer the possibility of avoiding macrophage-induced PD-1 resistance.
• Possible oral bioavailability (parenteral route common to mAbs).
• Simple and well-defined structure and stability (compared to complex mAbs).
• High manufacturing and scale-up feasibility (single entity, high chemical purity, standard analytical methods).
• Greater diffusion rate within the tumor microenvironment (compared to mAbs).
• Improved pharmacokinetics and pharmacodynamics (intracellular targets in addition to the extracellular ones, compared to mAbs).
• More affordable and accessible than mAbs.

• Our small molecule drug candidates inhibit PD-1/PD-L1 interaction and lead to the activation of tumor-infiltrating T cells.
• The possibility of immune checkpoint modulation following a small molecule-based approach can revolutionize immunotherapeutic approaches by overcoming some of the mAb limitations, such as limited tumor microenvironment diffusion.
• Small molecules are generally less expensive to produce, making them accessible to many. Therefore, these small-molecule drug candidates are promising tools and potential off-the-shelf products to enhance immune checkpoint clinical outcomes.


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