{"doi":"10.1101/2023.06.16.545220","title":"A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity","abstract":"The 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":392447,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":426844,"name":"Eric Tran","orcid":"0000-0002-6429-5923","position":1,"is_corresponding":false},{"id":630026,"name":"Xin Du","orcid":"0000-0002-9682-1211","position":2,"is_corresponding":false},{"id":662145,"name":"Jiajun Dong","orcid":"0000-0002-6901-5070","position":3,"is_corresponding":false},{"id":1022198,"name":"Harrison Sudholz","orcid":"0009-0000-6848-4230","position":4,"is_corresponding":false},{"id":745227,"name":"Hao Chen","orcid":"0000-0002-2070-5062","position":5,"is_corresponding":false},{"id":1021288,"name":"Zihan Qu","orcid":"0009-0004-8446-8459","position":6,"is_corresponding":false},{"id":1022199,"name":"Nicholas D. Huntington","orcid":"0000-0002-5267-7211","position":7,"is_corresponding":false},{"id":1022200,"name":"Jeffrey J. Babon","orcid":"0000-0002-5408-6239","position":8,"is_corresponding":false},{"id":1022201,"name":"Nadia J. Kershaw","orcid":"0000-0002-3554-2622","position":9,"is_corresponding":false},{"id":236994,"name":"Zhong‐Yin Zhang","orcid":"0000-0002-3234-0769","position":10,"is_corresponding":false},{"id":513055,"name":"Jonathan B. Baell","orcid":"0000-0003-2114-8242","position":11,"is_corresponding":false},{"id":630024,"name":"Florian Wiede","orcid":"0000-0001-5145-7180","position":12,"is_corresponding":false},{"id":630034,"name":"Tony Tiganis","orcid":"0000-0002-8065-9942","position":13,"is_corresponding":false},{"id":1022197,"name":"Shuwei Liang","orcid":"0000-0002-0359-505X","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T01:18:56.730121Z","pmid":"37397992","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}