Investigating CTLA‐4 binding to generate novel small‐molecule inhibitor

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The CTLA‐4 receptor may be found on the plasma membranes of T‐cells where it acts as a negative regulator of T‐cell activation. When CTLA‐4 receptors bind B7 ligands (CD80/86) found on antigen presenting cells, they activate signaling pathways which, in combination with signaling from T‐cell receptors bound to antigen‐carrying MHC proteins, decrease the inflammatory response. Regulatory T‐cells (Tregs) constitutively express CTLA‐4 on their membranes and have T‐cell receptors that recognize self‐antigens; this allows them to moderate the self‐tolerance of the immune system. Specifically, CTLA‐4 signaling in Tregs leads to the release of anti‐inflammatory cytokines which decrease the proliferation of helper and cytotoxic T‐cells and prevent monocytes, macrophage precursors, from differentiating into macrophages that would produce pro‐inflammatory cytokines. Unfortunately, it is frequently the case that Tregs recognizing cancerous cells accumulate within tumors. This leads to the inability of the body to form an immune reaction against the cancer. For this reason, cancer therapies which inhibit CTLA‐4 signaling are being developed. Current strategies to limit CTLA‐4 signaling have been successful in treating multiple forms of cancer but primarily rely on reducing CTLA‐4 interactions with B7 through monoclonal antibody therapy targeting the extracellular domain of CTLA‐4. Monoclonal antibodies are not particularly convenient as they must be administered through IV infusion and some formulations carry the risk of inducing serum‐sickness, in which the immune system develops a reaction against the foreign anti‐CTLA4 antibodies. However, instead of inhibiting CTLA‐4 binding to B7 with an antibody, it may be possible to inhibit the intracellular signaling of CTLA‐4 that occurs after this binding with a small molecule that is easier to administer. One of the main proteins that binds to and is activated by stimulated CTLA4 receptors is the phosphatase SHP2. SHP2 uses an SH2 domain at its N‐terminus to bind CTLA‐4 through the YVKM motif of the latter. Binding causes a conformational change in the SH2 domain which makes the phosphatase active site on an adjacent domain of SHP2 more accessible. This conformational change also causes SHP2 to unbind from CTLA‐4 so that a new protein can take its place to be activated. Activated SHP2 dephosphorylates many cytoplasmic proteins at their tyrosine residues leading to Treg activation and thus decreased inflammatory response.