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Ivosidenib, used to treat acute myeloid leukemia, acts on a common cancer\u2010linked variant of isocitrate dehydrogenase 1 (IDH1 R132H) inhibiting its \u201cgain\u2010of\u2010function\u201d activity\u2014the undesired reduction of 2\u2010oxoglutarate (2OG) to the oncometabolite 2\u2010hydroxyglutarate (2HG). The e\u2010Leaf quantifies the kinetics of IDH1 R132H inhibition across a wide and continuous range of conditions, efficiently revealing factors underlying the inhibitor residence time. Selective inhibition of IDH1 R132H by Ivosidenib and another inhibitor, Novartis 224, is readily resolved as a two\u2010stage process whereby initial rapid non\u2010inhibitory binding is followed by a slower step to give the inhibitory complex. These kinetic features are likely present in other allosteric inhibitors of IDH1\/2. Such details, essential for understanding inhibition mechanisms, are not readily resolved in conventional steady\u2010state kinetics or by techniques that rely only on measuring binding. Extending the new method and analytical framework presented here to other enzyme systems will be straightforward and should rapidly reveal insight that is difficult or often impossible to obtain using other methods.<\/jats:p>","DOI":"10.1002\/anie.202309149","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T13:01:54Z","timestamp":1692622914000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Electrochemical Nanoreactor Provides a Comprehensive View of Isocitrate Dehydrogenase Cancer\u2010drug Kinetics"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7935-6269","authenticated-orcid":false,"given":"Ryan A.","family":"Herold","sequence":"first","affiliation":[{"name":"Inorganic Chemistry Laboratory Department of Chemistry University of Oxford South Parks Road Oxford OX1 3QR UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0290-6565","authenticated-orcid":false,"given":"Christopher J.","family":"Schofield","sequence":"additional","affiliation":[{"name":"Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford Mansfield Road Oxford OX1 3QY UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8041-2491","authenticated-orcid":false,"given":"Fraser A.","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Inorganic Chemistry Laboratory Department of Chemistry University of Oxford South Parks Road Oxford OX1 3QR UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,12]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.2c00397"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpclett.1c01517"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20403-w"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201814370"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.1c01198"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7SC00850C"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1063\/5.0024701"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2214123120"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-021-00880-2"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2020.06.012"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2012.01.013"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08617"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01566-0"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32436-4"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi400514k"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.08.068"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.217406.113"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.01.020"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20210277"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-12630-x"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2017.12.005"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-018-0978-3"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1234769"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.040"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-1034"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.608497"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.9b00509"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1930"},{"key":"e_1_2_8_29_1","first-page":"17","volume":"66","author":"Liu S.","year":"2023","journal-title":"J. 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