8skl
From Proteopedia
PTP1B in complex with 182
Structural highlights
FunctionPTN1_HUMAN Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion.[1] [2] Publication Abstract from PubMedThe inhibition of protein tyrosine phosphatases (PTPs), such as PTP1B and PTPN2 that function as intracellular checkpoints, has emerged as an exciting new approach for bolstering T cell anti-tumor immunity to combat cancer. ABBV-CLS-484 is a dual PTP1B and PTPN2 inhibitor currently in clinical trials for solid tumors. Here we have explored the therapeutic potential of targeting PTP1B and PTPN2 with a related small molecule inhibitor, Compound 182. We demonstrate that Compound 182 is a highly potent and selective active site competitive inhibitor of PTP1B and PTPN2 that enhances antigen-induced T cell activation and expansion ex vivo and represses the growth of syngeneic tumors in C57BL/6 mice without promoting overt immune-related toxicities. Compound 182 repressed the growth of immunogenic MC38 colorectal and AT3-OVA mammary tumors as well as immunologically cold AT3 mammary tumors that are largely devoid of T cells. Treatment with Compound 182 increased both the infiltration and activation of T cells, as well as the recruitment of NK cells and B cells that promote anti-tumor immunity. The enhanced anti-tumor immunity in immunogenic AT3-OVA tumors could be ascribed largely to the inhibition of PTP1B/PTPN2 in T cells, whereas in cold AT3 tumors, Compound 182 elicited both direct effects on tumor cells and T cells to facilitate T cell recruitment and thereon activation. Importantly, treatment with Compound 182 rendered otherwise resistant AT3 tumors sensitive to anti-PD1 therapy. Our findings establish the potential for small molecule active site inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer. A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity.,Liang S, Tran E, Du X, Dong J, Sudholz H, Chen H, Qu Z, Huntington N, Babon J, Kershaw N, Zhang ZY, Baell J, Wiede F, Tiganis T bioRxiv. 2023 Jun 28:2023.06.16.545220. doi: 10.1101/2023.06.16.545220. Preprint. PMID:37397992[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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