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We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the “DFG-out” conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance."},"field_of_science":[{"id":"e9745cdf-d0e1-4797-8fee-3324e5b2bee2","url":"http://www.yso.fi/onto/okm-tieteenala/ta1182","in_scheme":"http://www.yso.fi/onto/okm-tieteenala/conceptscheme","pref_label":{"en":"Biochemistry, cell and molecular biology","fi":"Biokemia, solu- ja molekyylibiologia","sv":"Biokemi, cell- och molekylärbiologi"}},{"id":"a006e4cc-b051-4d1c-b94c-e1655d8888bc","url":"http://www.yso.fi/onto/okm-tieteenala/ta3111","in_scheme":"http://www.yso.fi/onto/okm-tieteenala/conceptscheme","pref_label":{"en":"Biomedicine","fi":"Biolääketieteet","sv":"Biomedicinska vetenskaper"}}],"infrastructure":[],"issued":"2023-06-21","keyword":["Biomedicine","Biochemistry cell and molecular biology"],"language":[{"id":"ec748146-3403-4a7f-adfe-bdbb1b889372","url":"http://lexvo.org/id/iso639-3/eng","in_scheme":"http://lexvo.org/id/","pref_label":{"en":"English","fi":"englanti","sv":"engelska"}}],"metadata_owner":{"id":"eb8aa44e-e16b-4c6c-ae4d-b9be524b58ed","organization":"service_tuni"},"other_identifiers":[{"notation":"b8cfde72-2640-4c56-be75-bb34fb7a3d9b","metax_ids":[]}],"persistent_identifier":"doi:10.2210/pdb7TEU/pdb","pid_generated_by_fairdata":false,"projects":[],"provenance":[],"relation":[],"remote_resources":[],"spatial":[],"state":"published","temporal":[],"theme":[],"title":{"en":"Crystal structure of JAK2 JH1 with type II inhibitor YLIU-04-105-1"},"created":"2025-01-28T16:52:35Z","modified":"2025-05-12T01:47:10Z","dataset_versions":[{"id":"68d6b839-ea36-4d70-927e-931857214c1f","title":{"en":"Crystal structure of JAK2 JH1 with type II inhibitor YLIU-04-105-1"},"persistent_identifier":"doi:10.2210/pdb7TEU/pdb","state":"published","created":"2025-01-28T16:52:35Z","version":1}],"published_revision":3,"version":1,"api_version":3,"metadata_repository":"Fairdata","record_created":"2025-01-28T16:52:36Z","record_modified":"2025-05-12T01:47:11Z"}]}