{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T22:29:28Z","timestamp":1786487368316,"version":"build-2736575974"},"reference-count":39,"publisher":"Elsevier BV","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010029","name":"Taishan Scholar Foundation of Shandong Province","doi-asserted-by":"publisher","award":["tstp.20230606"],"award-info":[{"award-number":["tstp.20230606"]}],"id":[{"id":"10.13039\/501100010029","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22477070"],"award-info":[{"award-number":["22477070"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22377068"],"award-info":[{"award-number":["22377068"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014103","name":"Key Technology Research and Development Program of Shandong Province","doi-asserted-by":"publisher","award":["2025CXPT121"],"award-info":[{"award-number":["2025CXPT121"]}],"id":[{"id":"10.13039\/100014103","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2023ZD0507700"],"award-info":[{"award-number":["2023ZD0507700"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2023ZD0507704"],"award-info":[{"award-number":["2023ZD0507704"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Acta Pharmaceutica Sinica B"],"published-print":{"date-parts":[[2026,8]]},"DOI":"10.1016\/j.apsb.2026.05.025","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T16:20:47Z","timestamp":1779812447000},"page":"5383-5404","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing pyrazine-2-carboxamide derivatives as dual FLT3\/HDAC inhibitors with enhanced pharmacokinetics and immunotherapeutic potential"],"prefix":"10.1016","volume":"16","author":[{"given":"Yingjie","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huirui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchao","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixue","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1830-338X","authenticated-orcid":false,"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8346-9001","authenticated-orcid":false,"given":"Xuben","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.apsb.2026.05.025_bib1","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.3324\/haematol.2015.129577","article-title":"Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib\/II panobidara study","volume":"100","author":"Ocio","year":"2015","journal-title":"Haematologica"},{"key":"10.1016\/j.apsb.2026.05.025_bib2","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1186\/s12967-025-06361-1","article-title":"Vorinostat impairs the cancer-driving potential of leukemia-secreted extracellular vesicles","volume":"23","author":"Massaro","year":"2025","journal-title":"J Transl Med"},{"key":"10.1016\/j.apsb.2026.05.025_bib3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40164-023-00383-5","article-title":"Synergistic effect of HDAC inhibitor chidamide with cladribine on cell cycle arrest and apoptosis by targeting HDAC2\/c-Myc\/RCC1 axis in acute myeloid leukemia","volume":"12","author":"Gu","year":"2023","journal-title":"Exp Hematol Oncol"},{"key":"10.1016\/j.apsb.2026.05.025_bib4","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1200\/JCO.21.01815","article-title":"Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the Ro-CHOP phase III study (conducted by LYSA)","volume":"40","author":"Bachy","year":"2022","journal-title":"J Clin Oncol"},{"key":"10.1016\/j.apsb.2026.05.025_bib5","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1016\/j.apsb.2023.02.007","article-title":"Targeting histone deacetylases for cancer therapy: trends and challenges","volume":"13","author":"Liang","year":"2023","journal-title":"Acta Pharm Sin B"},{"key":"10.1016\/j.apsb.2026.05.025_bib6","doi-asserted-by":"crossref","first-page":"12460","DOI":"10.1021\/acs.jmedchem.0c00830","article-title":"Thirty years of HDAC inhibitors: 2020 insight and hindsight","volume":"63","author":"Ho","year":"2020","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib7","doi-asserted-by":"crossref","first-page":"811","DOI":"10.3324\/haematol.2022.280996","article-title":"Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results","volume":"108","author":"Rai","year":"2022","journal-title":"Haematologica"},{"key":"10.1016\/j.apsb.2026.05.025_bib8","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/s41589-022-01015-5","article-title":"Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target","volume":"18","author":"Lechner","year":"2022","journal-title":"Nat Chem Biol"},{"key":"10.1016\/j.apsb.2026.05.025_bib9","doi-asserted-by":"crossref","DOI":"10.1016\/j.tranon.2023.101779","article-title":"Defining cellular responses to HDAC-selective inhibitors reveals that efficient targeting of HDAC3 is required to elicit cytotoxicity and overcome na\u00efve resistance to pan-HDACi in diffuse large B cell lymphoma","volume":"39","author":"Havas","year":"2024","journal-title":"Transl Oncol"},{"key":"10.1016\/j.apsb.2026.05.025_bib10","doi-asserted-by":"crossref","first-page":"5209","DOI":"10.1038\/s41467-024-49573-7","article-title":"Acetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors","volume":"15","author":"Sun","year":"2024","journal-title":"Nat Commun"},{"key":"10.1016\/j.apsb.2026.05.025_bib11","doi-asserted-by":"crossref","DOI":"10.1172\/JCI165448","article-title":"Combined HDAC8 and checkpoint kinase inhibition induces tumor-selective synthetic lethality in preclinical models","volume":"134","author":"Chang","year":"2024","journal-title":"J Clin Investig"},{"key":"10.1016\/j.apsb.2026.05.025_bib12","doi-asserted-by":"crossref","first-page":"4701","DOI":"10.1021\/acs.jmedchem.9b02161","article-title":"Discovery of peptide boronate derivatives as histone deacetylase and proteasome dual inhibitors for overcoming Bortezomib resistance of multiple myeloma","volume":"63","author":"Zhou","year":"2020","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib13","doi-asserted-by":"crossref","first-page":"12083","DOI":"10.1021\/acs.jmedchem.0c01454","article-title":"HDAC\u2013Bax multiple ligands enhance Bax-dependent apoptosis in HeLa cells","volume":"63","author":"Liang","year":"2020","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib14","doi-asserted-by":"crossref","first-page":"12200","DOI":"10.1021\/acs.jmedchem.2c00866","article-title":"Discovery of novel Src Homology-2 domain-containing phosphatase 2 and histone deacetylase dual inhibitors with potent antitumor efficacy and enhanced antitumor immunity","volume":"65","author":"Liu","year":"2022","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib15","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.1021\/acs.jmedchem.1c02225","article-title":"Discovery of DNA-targeting HDAC inhibitors with potent antitumor efficacy in vivo that trigger antitumor immunity","volume":"65","author":"Chen","year":"2022","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib16","doi-asserted-by":"crossref","first-page":"16480","DOI":"10.1021\/acs.jmedchem.4c01310","article-title":"Development of a first-in-class DNMT1\/HDAC inhibitor with improved therapeutic potential and potentiated antitumor Immunity","volume":"67","author":"Chang","year":"2024","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40164-025-00605-y","article-title":"IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response","volume":"14","author":"Yao","year":"2025","journal-title":"Exp Hematol Oncol"},{"key":"10.1016\/j.apsb.2026.05.025_bib18","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/s41408-023-00911-w","article-title":"Treatment of older adults with FLT3-mutated AML: emerging paradigms and the role of frontline FLT3 inhibitors","volume":"13","author":"Short","year":"2023","journal-title":"Blood Cancer J"},{"key":"10.1016\/j.apsb.2026.05.025_bib19","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1182\/blood-2014-05-578070","article-title":"Differential impact of allelic ratio and insertion site in FLT3-ITD\u2013positive AML with respect to allogeneic transplantation","volume":"124","author":"Schlenk","year":"2014","journal-title":"Blood"},{"key":"10.1016\/j.apsb.2026.05.025_bib20","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00277-011-1280-6","article-title":"Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML)","volume":"91","author":"Schneider","year":"2012","journal-title":"Ann Hematol"},{"key":"10.1016\/j.apsb.2026.05.025_bib21","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1182\/blood.V97.8.2434","article-title":"Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies","volume":"97","author":"Yamamoto","year":"2001","journal-title":"Blood"},{"key":"10.1016\/j.apsb.2026.05.025_bib22","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1200\/JCO.22.00715","article-title":"Prognostic value of FLT3-internal tandem duplication residual disease in acute myeloid leukemia","volume":"41","author":"Grob","year":"2022","journal-title":"J Clin Oncol"},{"key":"10.1016\/j.apsb.2026.05.025_bib23","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1182\/blood.2019003988","article-title":"Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML","volume":"135","author":"Dinardo","year":"2020","journal-title":"Blood"},{"key":"10.1016\/j.apsb.2026.05.025_bib24","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/nature11016","article-title":"Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia","volume":"485","author":"Smith","year":"2012","journal-title":"Nature"},{"key":"10.1016\/j.apsb.2026.05.025_bib25","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2024.116847","article-title":"Simultaneous inhibition of FLT3 and HDAC by novel 6-ethylpyrazine-2-carboxamide derivatives provides therapeutic advantages in acute myelocytic leukemia","volume":"279","author":"Chang","year":"2024","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib26","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41420-025-02417-9","article-title":"Antitumor activity of gilteritinib, an inhibitor of AXL, in human solid tumors","volume":"11","author":"Zhang","year":"2025","journal-title":"Cell Death Discov"},{"key":"10.1016\/j.apsb.2026.05.025_bib27","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1038\/nsmb.1899","article-title":"Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining","volume":"17","author":"Miller","year":"2010","journal-title":"Nat Struct Mol Biol"},{"key":"10.1016\/j.apsb.2026.05.025_bib28","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41419-024-06419-w","article-title":"CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma","volume":"15","author":"Li","year":"2024","journal-title":"Cell Death Dis"},{"key":"10.1016\/j.apsb.2026.05.025_bib29","doi-asserted-by":"crossref","first-page":"e2411888","DOI":"10.1002\/advs.202411888","article-title":"RNASET2 deficiency induces hepatocellular carcinoma metastasis through cholesterol-triggered MET activation","volume":"12","author":"Xu","year":"2025","journal-title":"Adv Sci"},{"key":"10.1016\/j.apsb.2026.05.025_bib30","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/s41419-023-06271-4","article-title":"The p53\/ZEB1-PLD3 feedback loop regulates cell proliferation in breast cancer","volume":"14","author":"Liu","year":"2023","journal-title":"Cell Death Dis"},{"key":"10.1016\/j.apsb.2026.05.025_bib31","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.immuni.2008.10.009","article-title":"Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8 T cell tolerance and permits effective immunity","volume":"29","author":"Keller","year":"2008","journal-title":"Immunity"},{"key":"10.1016\/j.apsb.2026.05.025_bib32","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1186\/s12885-021-08456-6","article-title":"Elevated TYROBP expression predicts poor prognosis and high tumor immune infiltration in patients with low-grade glioma","volume":"21","author":"Lu","year":"2021","journal-title":"BMC Cancer"},{"key":"10.1016\/j.apsb.2026.05.025_bib33","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1158\/1535-7163.MCT-18-1068","article-title":"HDAC3 inhibition upregulates PD-L1 expression in B-cell lymphomas and augments the efficacy of anti-PD-L1 therapy","volume":"18","author":"Deng","year":"2019","journal-title":"Mol Cancer Ther"},{"key":"10.1016\/j.apsb.2026.05.025_bib34","doi-asserted-by":"crossref","DOI":"10.1002\/mco2.70500","article-title":"Preclinical characterization of SDFZ-8, a highly potent HDAC1 inhibitor, for cancer immunotherapy","volume":"6","author":"Zhou","year":"2025","journal-title":"MedComm"},{"key":"10.1016\/j.apsb.2026.05.025_bib35","doi-asserted-by":"crossref","first-page":"5736","DOI":"10.1021\/acs.jmedchem.4c03084","article-title":"Design, synthesis, and biological evaluation of novel Fms-like tyrosine kinase 3\/VEGFR2\/histone deacetylase inhibitors for the treatment of acute myeloid leukemia","volume":"68","author":"Tian","year":"2025","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib36","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2023.115759","article-title":"Rational discovery of dual FLT3\/HDAC inhibitors as a potential AML therapy","volume":"260","author":"Wang","year":"2023","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib37","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1177\/1087057106296047","article-title":"Three mechanistically distinct kinase assays compared: measurement of intrinsic ATPase activity identified the most comprehensive set of ITK inhibitors","volume":"12","author":"Kashem","year":"2007","journal-title":"J Biomol Screen"},{"key":"10.1016\/j.apsb.2026.05.025_bib38","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: a new approach for rapid, accurate docking and scoring 1 method and assessment of docking accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J Med Chem"},{"key":"10.1016\/j.apsb.2026.05.025_bib39","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF chimera\u2013A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J Comput Chem"}],"container-title":["Acta Pharmaceutica Sinica B"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2211383526003187?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2211383526003187?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T21:53:44Z","timestamp":1786485224000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2211383526003187"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":39,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["S2211383526003187"],"URL":"https:\/\/doi.org\/10.1016\/j.apsb.2026.05.025","relation":{},"ISSN":["2211-3835"],"issn-type":[{"value":"2211-3835","type":"print"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Optimizing pyrazine-2-carboxamide derivatives as dual FLT3\/HDAC inhibitors with enhanced pharmacokinetics and immunotherapeutic potential","name":"articletitle","label":"Article Title"},{"value":"Acta Pharmaceutica Sinica B","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.apsb.2026.05.025","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.","name":"copyright","label":"Copyright"}]}}