First-in-Class Small Molecule BTLA Inhibitors as Potential Cancer Therapies
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Brian Kuo
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Modern cancer treatments have developed to a great extent — however, various factors such as cancer types and resistance continue to make effective treatments difficult to create for many cancers. Among different cancer treatments, immunotherapy shows promise because of its utilization of one’s own body’s immune system in fighting off cancerous cells. Immune checkpoints instruct the body to stop producing anti-cancer cells, and blocking these checkpoints can be effective in reactivating an immune system. B and T Lymphocyte Attenuator (BTLA) is an immune checkpoint that shows promise as an immunotherapy target, but current clinical trials focus solely on large monoclonal antibodies that can have severe side effects and other limitations due to larger molecular size. By identifying small molecule BTLA inhibitors, the development of anti-cancer immunotherapy treatments could be vastly improved. In this paper I utilize a variety of experiments to virtually screen small molecules and identify potential BTLA inhibitors. First, I located suitable binding sites in BTLA using 3 different methods (geometric, energetic, and machine learning methods). I identified compounds using virtual screening in two different experiments, by identifying HVEM B-chain pharmacophore maps, then scanning the ZINC compound library for matches. Then, I verified the compounds’ site binding on BTLA with molecular docking in SwissDock. Finally, the druggability of the remaining compounds were evaluated twice, for drug properties and for toxicity, in SwissADME and ProTox 3.0 respectively. In the end, two promising compounds with favorable energetic interactions with BTLA, strong drug properties according to Lipinski’s rule, and low toxicity were identified as drug candidates for different applications, which hold potential for being pivotal milestones in the field of cancer therapy.
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Authors
Brian Kuo
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