{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T06:32:39Z","timestamp":1787639559642,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Plan Project of Ningbo City","award":["2023S048"],"award-info":[{"award-number":["2023S048"]}]},{"name":"Science and Technology Plan Project of Ningbo City","award":["2022S128"],"award-info":[{"award-number":["2022S128"]}]},{"DOI":"10.13039\/501100008867","name":"Zhejiang Provincial Department of Education","doi-asserted-by":"publisher","award":["Y202456631"],"award-info":[{"award-number":["Y202456631"]}],"id":[{"id":"10.13039\/501100008867","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020346","name":"Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Development Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100020346","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Epigenetics garnered significant scientific interest in recent decades, with histone acetylation emerging as the most prevalent epigenetic deregulation process observed in malignancies. The clinical application of histone deacetylase (HDAC) inhibitors faced challenges, including complex therapeutic mechanisms and inconsistent treatment outcomes. In Acute Lymphoblastic Leukemia (ALL), the dysregulation of HDAC activity presents a promising therapeutic target. To investigate cellular-level tumor suppression by HDAC inhibitors possessing potent target engagement, we developed two novel azetidine-hydroxamic acid conjugates. Compared to N-hydroxy-4-((quinolin-4-ylamino)methyl)benzamide (NBU-1), N-hydroxy-6-((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl)amino)hexanamide (NBU-2) demonstrated enhanced inhibitory activity against HDAC1 (class I) and HDAC6 (class II) with IC50 values of 7.75 nM and 7.34 nM, respectively, consistent with binding mode analysis and docking energy calculations. In vitro evaluation across 12 tumor cell lines revealed NBU-2\u2019s potent antiproliferative effects, particularly against the ALL-derived Jurkat cells (IC50 = 0.86 \u03bcM). Subsequent mechanistic studies were therefore conducted in this ALL model. Proteomic profiling indicated its potential involvement in modulating AKT signaling and histone modification pathways in Jurkat cells. Mechanistic investigations demonstrated that NBU-2 elevated histone acetylation while suppressing AKT phosphorylation. This compound altered apoptotic regulators by downregulating Bcl-2 and Bcl-XL expression while upregulating BAX, ultimately activating Caspase-9 and Caspase-3 to induce apoptosis. Cell cycle analysis revealed NBU-2-mediated G0\/G1 arrest through reduced expression of Cyclin D1 and CDK4, diminished Rb protein phosphorylation, and increased p21 expression. These findings propose a strategic framework for developing next-generation HDAC inhibitors for ALL treatment and elucidating their mechanism-specific anti-cancer actions.<\/jats:p>","DOI":"10.3390\/cells14221822","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T10:30:59Z","timestamp":1763634659000},"page":"1822","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Nitrogen Heterocycle\u2013Hydroxamic Acid Conjugates Demonstrating Potent Anti-Acute Lymphoblastic Leukemia Activity: Induction of Endogenous Apoptosis and G0\/G1 Arrest via Regulation of Histone H3 Acetylation and AKT Phosphorylation in Jurkat Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Lingjie","family":"Wu","sequence":"first","affiliation":[{"name":"School of Pharmacy, Health Science Center, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaojie","family":"Lou","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4371-4746","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Health Science Center, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5625-5358","authenticated-orcid":false,"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Drug Discovery Technology, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1182\/asheducation-2016.1.580","article-title":"T-cell acute lymphoblastic leukemia","volume":"1","author":"Raetz","year":"2016","journal-title":"Hematol. 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