Potent Small Molecule PD-1/PD-L1 Interaction Inhibitors for Cancer Immunotherapy

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Purdue University researchers have developed a potent small molecule for use in cancer immunotherapy which acts by inhibiting the Programmable Cell Death Protein 1/Programmable Death-Ligand 1 (PD-1/PD-L1) interaction. Cancer cells express PD-L1, a cell surface protein that binds to PD-1 on T-cells, debilitating anti-cancer immunity. Antibodies targeting the PD-1/PD-L1 interaction have proven to be a viable therapeutic strategy toward mitigating cancer growth but suffer from high production costs, limited administration techniques, and low therapeutic indices. To address these limitations, Purdue University researchers created a small molecule inhibitor of the PD-1/PD-L1 interaction that specifically target PD-1 dimerization. The researchers developed the new molecule through robust computational modeling of publicly available PD-1/PD-L1 inhibitory data. In homogenous time-resolved fluorescence binding assays the Purdue compound exhibited about 1.6 fold increased potency in inhibiting the PD-1/PD-L1 interaction compared to a positive control molecule known from the patent literature (IC50 = 339.9 nM and 521.5 nM, respectively). Further medicinal chemistry optimization promises to increase potency and yield an excellent preclinical candidate for use in small molecule immune checkpoint blockade therapy.

-Increased Potency to PD-1/PD-L1 Interaction
-Combined Scaffolds of BMS Compounds

Potential Applications:
-Immune Checkpoint Blockade
-Cancer Therapeutics

Related Publication:
Combined Molecular Graph Neural Network and Structural Docking Selects Potent Programmable Cell Death Protein 1/Programmable Death-Ligand 1 (PD-1/PD-L1) Small Molecule Inhibitors
Preprint available at chemrixiv.org
DOI: 10.26434/chemrxiv.12083907.v1
Mar 5, 2021
PCT-Gov. Funding

Mar 11, 2020
Provisional-Gov. Funding
United States
Purdue Office of Technology Commercialization
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