ABPP-PROTDRUG · An Activity-based Protein Profiling-supported Protein Therapeutic Drug discovery platform for the development of innovative anti-cancer therapies based on Lin28 inhibition

An Activity-based Protein Profiling-supported Protein Therapeutic Drug discovery platform for the development of innovative anti-cancer therapies based on Lin28 inhibition

Cancer remains one of the most prevalent diseases worldwide and new therapeutic targets are highly sought. Many proteins or protein-associated molecular pathways have relevant roles in many cancers, making research in cancer-associated protein-based therapies a popular area. In this project, we aim to take advantage of cancer-associated protein-protein interactions and develop innovative therapeutics for cancer treatment. Certain proteins in our cells interact amongst each other, often only temporarily, and this interactions can result in both anti-cancer effects or cancer potentiating effects. We aimed to perform small chemical modifications in proteins that will allow them to form irreversible chemical connections with their targets, stabilizing their interaction and potentiating these effects. This process will translate into more potent anti-cancer effects due the irreversible nature of the new bond. The successful development of these agents will effectively contribute to the field of protein therapeutics, or protein drugs, a novel class of therapeutic strategy. Our approach focused on the PD-1/PD-L1 interaction. PD-L1 is frequently overexpressed in tumors and PD-1 is a protein that interacts with it, with the interaction between both proteins leading to inhibition of immune system cells, release of cytokines and general cellular toxicity, leading to increased cell death of important immune cells. Interrupting this interaction via the use of protein drugs has been shown to lead to reduction in tumor growth in mice. We focused our project in creating protein drugs that interact with PD-L1 in an irreversible manner, keeping PD-1 and PD-L1 from interacting and overall leading to an anti-cancer effect. The success of our project will translate into better therapeutics for cancer patients and better quality of life for people suffering from cancer. The targeting of unusual proteins with innovative tools might be advantageous for cancers where conventional therapies fail. Innovative cancer therapies will also alleviate the economic burden of cancer, with the potential of improving patient care by allowing better allocating of medical resources. Despite focusing solely on cancer in this project, the concept of interfering with protein-protein interactions is present virtually in all cell processes both in heathy states and diseased states. We believe the popularization of these techniques will allow its application in other diseases, creating further impact at a society level and generating numerous other projects both in the host lab and in other labs. Our main project objectives were: (i) Create a library of protein drugs targeting PD-L1 using a variety of PD-L1 interacting proteins and chemistries developed in the host lab; (ii) Evaluate the binding of these proteins to PD-L1 and the stability of their interaction; (iii) Study the crosslinking between the protein drugs and PD-L1 using proteomics; (iv) Evaluate the biological effects of the protein drugs in cancer cells. In addition to these objectives we also developed other anti-cancer therapeutics like PROTACs, molecular condensate modulators and proteomics platforms to study anti-cancer agents.

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