Investigational New Drugs最新文献

{"title":"Beyond the obvious: targeting the SLC transportome and non-canonical drug transport mechanisms in cancer therapy.","authors":"Srikruthi Kunigal Sridhar, Kasim Sakran Abass, Buduru Gowthami, Nimbagal Raghavendra Naveen","doi":"10.1007/s10637-025-01577-w","DOIUrl":"https://doi.org/10.1007/s10637-025-01577-w","url":null,"abstract":"<p><p>The solute carrier (SLC) superfamily comprises a broad array of membrane-bound transport proteins that are integral to the intracellular uptake of various substrates, including nutrients, endogenous metabolites, and an expanding repertoire of anticancer drugs. Although they play a pivotal role in drug disposition and pharmacokinetics, SLC-mediated influx mechanisms have historically garnered less research attention compared to the extensively studied ATP-binding cassette (ABC) efflux transporters. Increasing evidence now indicates that the expression profiles, functional activity, and regulatory pathways of SLC transporters critically influence intracellular drug accumulation, therapeutic outcomes, and the emergence of resistance in cancer. This review presents an in-depth analysis of key SLC transporters, such as organic cation transporters (OCTs), organic anion transporting polypeptides (OATPs), L-type amino acid transporter 1 (LAT1), and the cystine/glutamate exchanger(xCT), which have demonstrated relevance in mediating the uptake of anticancer agents. We explore their structural features, cancer-specific expression dynamics, and known interactions with chemotherapeutic and molecularly targeted therapies. Additionally, unconventional drug transport routes, including lipid raft-assisted endocytosis, exosome-mediated cargo transfer, and ion channel-facilitated uptake, are discussed as potential contributors to drug delivery in tumor cells. The review further explores innovative therapeutic strategies that aim to harness SLC transporters for clinical benefit, including prodrug designs, nanoparticle-based delivery systems, and transporter-directed drug development. Clinical progress in targeting LAT1, xCT, and OATP family members is also reviewed, with a focus on ongoing trials. Finally, we address the current limitations in targeting SLCs, such as overlapping substrate specificity, tumor-specific heterogeneity, and interindividual genetic variations affecting transporter function. By framing SLCs as viable and strategic targets within the oncology drug development landscape, this review highlights their emerging potential in shaping future precision oncology initiatives.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical potential of antibody-drug conjugates in early-phase clinical trials for late-line treatment of advanced solid tumors.","authors":"Ippei Miyamoto, Takahiro Kogawa, Kana Kurokawa, Eriko Miyawaki, Yohei Arihara, Shota Fukuoka, Yukinori Ozaki, Makiko Ono, Mayu Yunokawa, Masumi Yamazaki, Naomi Hayashi, Ippei Fukada, Takayuki Ueno, Shunji Takahashi, Shigehisa Kitano","doi":"10.1007/s10637-025-01576-x","DOIUrl":"https://doi.org/10.1007/s10637-025-01576-x","url":null,"abstract":"<p><p>Recently, comprehensive genomic profiling (CGP)-matched therapy and antibody-drug conjugates (ADCs) have garnered increased attention. However, their response rates and prognoses in early-phase clinical trials are not yet widely appreciated in clinical practice. We conducted a retrospective chart review of patients with advanced solid tumors who enrolled in clinical trials as a late-line treatment in our department between January 2020 and December 2023. This study aimed to evaluate clinical outcomes, including overall response rate (ORR), disease control rate (DCR), overall survival (OS), and associated prognostic factors. A total of 574 cases were referred, including 173 in the late-line setting. The ADCs group achieved the highest ORR and DCR (31.9% and 68.1%, respectively). ADCs also demonstrated a longer median progression-free survival (PFS) compared to CGP-matched and other trials (median PFS: ADCs 4.0 months vs. CGP-matched trials 1.9 months vs. others 1.7 months; p = 0.001). Multivariate analysis identified ADCs as significantly associated with improved PFS, while CGP-matched therapy was associated with better OS. The findings suggest that, even in early phase clinical trials for the late-line setting, ADCs can enhance therapeutic responses. These results underscore the need to avoid overreliance on CGP outcomes and instead prioritize early referral to Phase 1 facilities, timely intervention, and the appropriate inclusion of patients to achieve optimal clinical outcomes.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the risks and benefits of investigational new drugs in adult phase-I oncology trials in China, 2013-2021.","authors":"Zhizhou Liang, Yu Yang, Yichen Zhang, Kexin Han, Huangqianyu Li, Luwen Shi, Xiaodong Guan","doi":"10.1007/s10637-025-01560-5","DOIUrl":"https://doi.org/10.1007/s10637-025-01560-5","url":null,"abstract":"<p><p>Previous research shows that the benefits of phase-I oncology trials increased from 5 to 18% between 2000 and 2019 globally. However, the risk-benefit profile of phase-I trials in China is unclear. This study aims to analyze the risk-benefit profile of phase-I oncology trials in China and explore their correlation. We included adult phase-I oncology trials registered on the Chinese Clinical Trial Registry and Information Disclosure Platform between September 2013 and December 2021. Data on response rates and grade-3/4 adverse events were retrieved from PubMed, Google Scholar, and CNKI to assess their correlation. A total of 189 trials with 9591 patients were analyzed. The median response rate was 25.4% (IQR, 9.4-41.4%), and the overall incidence of grade-3/4 adverse events was 29.3% (IQR, 15.0-43.8%). No significant trends were observed over time. Subgroup analysis showed higher response rates in lymphoma (45.8%), cell therapies (80.0%), and biomarker trials (38.0%). Higher adverse event rates were seen in breast cancer (55.0%), chemical drugs (33.3%), cytotoxic drugs (73.3%), and combination therapies (35.7%). A weak correlation was found between response rates and grade-3/4 adverse events (ρ = 0.217; p = 0.003), with a moderate correlation in immunotherapy (ρ = 0.417; p < 0.001). This is the first assessment of early efficacy and safety signals of phase-I oncology trials in China. No significant temporal trends were identified. However, the correlation in immunotherapy suggests that higher benefits may be accompanied by greater risks.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tackling tumor hypoxia: advances in breaking the oncogenic HIF-1α-p300/CBP alliance.","authors":"Emadeldin M Kamel, Sally Mostafa Khadrawy, Ahmed A Allam, Noha A Ahmed, Faris F Aba Alkhayl, Al Mokhtar Lamsabhi","doi":"10.1007/s10637-025-01570-3","DOIUrl":"https://doi.org/10.1007/s10637-025-01570-3","url":null,"abstract":"<p><p>The ability of tumor cells to survive under low-oxygen conditions is largely attributed to the hypoxia-inducible factor-1 (HIF-1) pathway, in which HIF-1α forms a functional complex with the transcriptional co-activators p300/CBP. This interaction drives the expression of genes that promote angiogenesis, metabolic reprogramming, and immune evasion and correlates with advanced disease and poor outcomes in diverse cancer types. In recent years, extensive efforts have sought to disrupt the HIF-1α-p300/CBP axis, leveraging strategies that include blocking protein-protein binding, inhibiting acetyltransferase activity, and modulating post-translational modifications that stabilize HIF-1α. A range of small-molecule inhibitors, derived either synthetically or from natural sources such as fungal metabolites and plant polyphenols, have demonstrated efficacy in preclinical cancer models by attenuating tumor hypoxia adaptations and sensitizing malignant cells to chemotherapies and radiotherapies. Although many of these compounds exhibit favorable anti-tumor activity, issues of specificity, drug delivery, toxicity, and potential resistance mechanisms remain. This review highlights the current understanding of HIF-1α-p300/CBP biology, examines small-molecule compounds that target this critical transcriptional interface, and evaluates preclinical evidence validating their therapeutic promise. We also discuss emerging challenges in translating these findings to clinical practice, emphasizing combination treatment strategies, biomarker-driven patient selection, and refined drug formulations to optimize efficacy and safety. By offering a detailed overview of the HIF-1α-p300/CBP landscape, this review underscores the potential of disabling tumor hypoxia responses as an innovative approach to combat cancer progression.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 1/2, open-label study of oral bacterial supplementation (EDP1503) plus pembrolizumab in participants with advanced or metastatic microsatellite-stable colorectal cancer, triple-negative breast cancer, and checkpoint inhibitor-relapsed tumors.","authors":"Judy S Wang, Edward R Arrowsmith, J Thaddeus Beck, Jennifer Friedmann, Rahima Jamal, Duncan McHale, Humphrey Gardner, Michael J Chisamore, Susanna V Ulahannan","doi":"10.1007/s10637-025-01573-0","DOIUrl":"10.1007/s10637-025-01573-0","url":null,"abstract":"<p><p>We report a phase 1/2 study evaluating EDP1503 (capsule containing Bifidobacterium animalis lactis) ± pembrolizumab in participants with microsatellite-stable colorectal cancer (MSS CRC), triple-negative breast cancer (TNBC), or other tumor types that relapsed after responding to immunotherapy (KEYNOTE-939/EDP1503-101; NCT03775850). Participants (≥ 18 years) had confirmed advanced/metastatic tumors and progressive disease (PD), were intolerant/nonresponsive to recommended treatment, and had measurable disease (RECIST v1.1). Cohorts were: MSS CRC (Cohort A), metastatic/locally advanced TNBC (Cohort B), and PD following partial response/stable disease for ≥ 6 months during anti‒PD-(L)1 therapy (≥ 8 months during anti‒PD-(L)1 therapy plus chemotherapy for non-small-cell lung cancer) (Cohort C). Participants received oral EDP1503 (2 or 4 capsules twice daily [BID]) for 2 weeks, then EDP1503 (2 or 4 capsules BID) plus intravenous pembrolizumab 200 mg every 3 weeks until PD, participant withdrawal, investigator decision, intolerable toxicity, or completion of 35 cycles. Primary endpoints were safety/tolerability, objective response rate (RECIST v1.1), and immune-response rate. Secondary endpoints included duration of clinical benefit, progression-free survival (PFS), and overall survival (OS). Of 69 participants, objective responses were observed in 3 (2 in Cohort B and 1 in Cohort C with partial responses received 4 capsules BID). For participants receiving 4 capsules BID, median duration of clinical benefit (95% CI) was 8.7 months (5.5 months‒not evaluable), median PFS was 1.8 (1.7‒1.9) months, and median OS was 7.8 (2.5‒13.5) months. Grade ≥ 3 adverse events occurred in 28 participants (40.6%), with no new safety signals. EDP1503 plus pembrolizumab had manageable safety but limited clinical activity.Trial registration: KEYNOTE-939, EDP1503-101 trial: ClinicalTrials.gov NCT03775850.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The multifaceted role of KIF15 in cancer progression and therapy.","authors":"Sarah Qutayba Badraldin, Karar H Alfarttoosi, Hayder Naji Sameer, Ashok Kumar Bishoyi, Subbulakshmi Ganesan, Aman Shankhyan, Subhashree Ray, Ahmed Yaseen, Zainab H Athab, Mohaned Adil","doi":"10.1007/s10637-025-01572-1","DOIUrl":"https://doi.org/10.1007/s10637-025-01572-1","url":null,"abstract":"<p><p>Kinesin family member 15 (KIF15), a kinesin superfamily motor protein, is known to be involved in mitotic spindle formation and chromosome movement during cell division. Recent research has determined KIF15 to be a crucial regulator in several oncogenic pathways and proposed that its role may extend beyond mere cell mechanics. Aberrant KIF15 expression has also been found to be involved in the onset of numerous cancers by promoting the proliferation, migration, and invasive abilities of cancer cells, thereby leading to increased metastatic capability. This review summarizes knowledge of the complex roles of KIF15 in cancer biology, highlighting its regulatory functions and interactions with key signaling pathways that control cell cycle kinetics and mechanisms for tumorigenesis. Moreover, the elevated levels of KIF15 in certain types of cancer make it an amenable target for therapy. New directions toward inhibiting activity or reducing the levels of KIF15 promise to restrict tumor growth, offering new hope for cancer treatment. This combined understanding of KIF15 functions stresses its importance not only in the fundamental processes of cell division but also in the developing field of cancer treatment, highlighting the ongoing necessity for extensive research into creating effective treatments targeted against KIF15 in oncology.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical characteristics, treatment and prognosis of pembrolizumab induced myocarditis.","authors":"Zhaoquan Wu, Wei Sun, Chunjiang Wang","doi":"10.1007/s10637-025-01575-y","DOIUrl":"https://doi.org/10.1007/s10637-025-01575-y","url":null,"abstract":"<p><p>To explore the regularity and clinical characteristics of pembrolizumab induced myocarditis, and to provide a reference for the diagnosis and treatment of myocarditis. Clinical reports of pembrolizumab induced myocarditis were collected by searching the database as of May 31, 2025. Clinical data were extracted and analyzed statistically. A total of 97 patients were enrolled in the study, with a median age of 70 years (range 25, 89), of which 53(54.6%) were male. The median time for diagnosis of myocarditis was 25 days (range 3, 4050). The common clinical symptoms were dyspnoea (23.7%), shortness of breath (16.5%), and thoracic pain (13.4%). Myositis and/or myasthenia gravis occurred in 43.3% of the patients. These patients with myocarditis may be accompanied by abnormalities in myocardial biomarkers, electrocardiograms, cardiac magnetic resonance and echocardiograms. After the patients discontinued pembrolizumab and received steroid-based immunotherapy, 72.2% of the patients recovered and 26.8% of the patients died. Myocarditis is a rare and fatal immune-related adverse event of pembrolizumab. Cardiac biomarkers, electrocardiograms and echocardiograms should be monitored during the use of Pembrolizumab. Cardiac magnetic resonance or myocardial biopsy can be used to further confirm myocarditis.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-CD47 tri-specific killer engager enhances NK cell cytotoxicity against lung cancer.","authors":"Chutipa Chiawpanit, Yupanun Wutti-In, Somsakul Pop Wongpalee, Ratchaneewan Sumankan, Peeranut Winidmanokul, Prin Sungwan, Seiji Okada, Naravat Poungvarin, Pa-Thai Yenchitsomanus, Aussara Panya","doi":"10.1007/s10637-025-01568-x","DOIUrl":"https://doi.org/10.1007/s10637-025-01568-x","url":null,"abstract":"<p><p>Lung cancer remains the leading cause of cancer-related deaths worldwide, with immune evasion posing a major therapeutic challenge. One key mechanism involves the 'don't eat me' signal mediated by the interaction between CD47 and signal regulatory protein alpha (SIRPα), which inhibits macrophage phagocytosis and natural killer (NK) cell cytotoxicity, facilitating tumor escape. To overcome this immune evasion, we developed a tri-specific killer engager (TriKE) targeting CD47, termed anti-CD47 TriKE, designed to enhance NK cell-mediated cytotoxicity against lung cancer cells. The activity of anti-CD47 TriKE was evaluated for its ability to induce NK cell proliferation and its binding affinity to NK cells and lung cancer cell lines (A549, NCI-H460, and NCI-H1975). At a concentration of 30 nM, anti-CD47 TriKE effectively promoted NK cell proliferation and exhibited strong binding to both NK cells and lung cancer cells. Functional assays in 2D and 3D co-culture models demonstrated that anti-CD47 TriKE significantly enhanced NK cell specificity and cytotoxicity. Notably, NK cell-mediated cytotoxicity correlated with the basal level of CD47 expression in target cells. In NCI-H1975 cells, which exhibit the highest CD47 expression, target cell viability was reduced by approximately 40%-a significantly greater reduction than in control groups. These findings highlight the potential of anti-CD47 TriKE as a promising immunotherapeutic strategy for lung cancer, particularly in targeting high-CD47-expressing tumor cells and overcoming immune evasion mechanisms.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic effects of the curcumin analog HO-3867 and olaparib in transforming fallopian tube epithelial cells.","authors":"Cai-Chieh Tseng, Min-Hsi Ku, Wei-Min Wu, Ava Mendez, Tessa Christner, Yun-Chieh Wu, Wei-Lun Huang, Yu-Hsiang Chen, Ching-Wen Huang, Johnathan Barefoot, Chi-Wei Chen","doi":"10.1007/s10637-025-01571-2","DOIUrl":"https://doi.org/10.1007/s10637-025-01571-2","url":null,"abstract":"<p><p>Ovarian cancer remains one of the most lethal gynecologic malignancies, largely due to high recurrence rates and treatment-related toxicities. Although PARP inhibitors like Olaparib have shown efficacy in BRCA-mutated cancers, their benefit is limited in broader patient populations. TP53 mutations, highly prevalent in ovarian cancer, promote tumor progression and resistance, making p53 a key therapeutic target. This study evaluated the anticancer potential of HO-3867, a curcumin analog known to restore mutant p53 function, alone and in combination with Olaparib. We used fallopian tube-derived ovarian cancer models harboring mutant or null TP53 and analyzed TP53 expression and mutation profiles using TCGA datasets. Molecular docking simulations and cellular thermal shift assays (CETSA) confirmed HO-3867 binding to the p53^Y220C mutant core domain. Cytotoxicity was assessed via SRB assays; flow cytometry and Western blotting were used to examine cell cycle progression, apoptosis, and DNA damage. HO-3867 treatment increased phospho-p53 (Ser15) and p21 expression, induced G1 phase arrest, and suppressed cell viability. Notably, co-treatment with Olaparib synergistically enhanced apoptosis, as indicated by increased caspase-3 and PARP1 cleavage and elevated γH2AX levels. These findings suggest that HO-3867 reactivates mutant p53 and potentiates Olaparib efficacy by promoting apoptosis and amplifying DNA damage, offering a promising therapeutic strategy for TP53-mutant ovarian cancer.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct functional HOXA9/DNA-binding competitors versus epigenetic inhibitors of HOXA9 expression on cell proliferation, death and differentiation processes in the model of MLL-rearranged acute myeloid leukemia.","authors":"Julie Vrevin, Mélanie Lambert, Marine Andrique, Nathalie Jouy, Marie-Hélène David-Cordonnier","doi":"10.1007/s10637-025-01561-4","DOIUrl":"https://doi.org/10.1007/s10637-025-01561-4","url":null,"abstract":"<p><p>Recent progress in cancer treatment has led to the development of advanced therapies targeting specific oncogenic drivers, with, for instance, new small molecule-targeted agents, antibody-drug conjugates, peptide drugs, cell-based, or gene therapies. The key target may be either the mutated/fused protein itself or a protein whose expression is directly dysregulated and involved in proliferation, resistance to cell death, or other cellular processes associated with the oncogenic process. Identifying the best therapeutic strategy requires evaluating both inhibitors of the altered protein and the dysregulated oncogene linked to the pathology. Within this context, the MLL-rearranged subtype (MLL-r) of acute myeloid leukemia (AML) poses significant challenges due to unfavorable prognosis, frequent relapses, and treatment resistance. MLL-r AMLs are known to be addicted to the oncogene transcription factor HOXA9, with a differentiation blockade that relies on its ability to bind DNA. Recently, several MLL-r epigenetic complex inhibitors have been developed, some entering clinical trials. We identified and optimized two HOXA9 functional inhibitors, DB818 and DB1055, operating at the DNA-binding level. The present study compares the cellular effects of both indirect (epigenetic MLL inhibitors) and direct (DNA binding) HOXA9 inhibitors in two distinct pediatric MLL-r cell models, THP-1 and MV4-11. Our findings indicate that direct DNA-binding inhibition of HOXA9 by DB818 and DB1055 resulted in more favorable outcomes in facilitating leukemic cell differentiation, impairing uncontrolled proliferation, and promoting cell death. Thus, a direct DNA-binding inhibition of the addiction oncogene HOXA9 could represent an interesting opportunity for MLL-r therapy.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}