fimepinostat (CUDC-907) / Curis - LARVOL DELTA

Large-scale drug screening identifies clinically actionable combinations to overcome BTK/PI3K inhibitor resistance in marginal zone lymphoma (AACR 2026) - "Here, we present data from a large pharmacological screen involving over 3,500 compounds in 2 MZL models with secondary resistance to BTK/PI3Ki, developed through prolonged exposure to idelalisib (Arribas 2022) or ibrutinib (Arribas 2025).Methods...Adding the alisertib (AURKAi), rigosertib (PLKi), fimepinostat (PI3K/HDACi), lanatoside-C (Na+K+ATPase), astragalin (apoptosis), astragaloside-I (WNT) and oridonin (AKT) was of benefit (additivity or synergism) in both parental and resistant cells.Conclusions...Several clinically advanced agents—particularly PAK4/NAMPT, AURKA, WNT, and Na⁺/K⁺-ATPase inhibitors—enhanced or restored the activity of BTKi/PI3Ki. These findings highlight new therapeutic strategies for relapsed/refractory MZL and support clinical evaluation of targeted combinations to overcome acquired resistance."

Clinical • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Oncology • AURKA • NAMPT

Fimepinostat Promotes Apoptosis and Decreases Cytokine Secretion in NF2-Related Human Schwannoma Cells. (PubMed, Int J Mol Sci) - "Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression."

Journal • Brain Cancer • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • CASP3 • CDKN1A • TNFRSF1A

Trametinib and Fimepinostat Induce Malignant Peripheral Nerve Sheath Tumor Cell Death In Vitro. (PubMed, Cancers (Basel)) - "These studies demonstrate in vitro efficacy for two candidate MPNST therapeutics which could reduce tumor burden and metastasis in NF1 patients."

Journal • Preclinical • Brain Cancer • Genetic Disorders • Melanoma • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • NF1

Trial of CUDC-907 in Children and Young Adults With Relapsed or Refractory Solid Tumors, CNS Tumors, or Lymphoma (clinicaltrials.gov) - P1 | N=26 | Completed | Sponsor: Dana-Farber Cancer Institute | Active, not recruiting ➔ Completed

Trial completion • B Cell Lymphoma • Brain Cancer • CNS Tumor • Glioma • Hematological Malignancies • Lymphoma • Neuroblastoma • Oncology • Solid Tumor • MYC • MYCN

Phosphatidylinositol-3-Kinase (PI3K) and Histone Deacetylase (HDAC) Multitarget Inhibitors: An Update on Clinical and Preclinical Candidates. (PubMed, Pharmaceuticals (Basel)) - "This review examines the rational design and synthetic evolution of dual PI3K/HDAC inhibitors, an area catalyzed by the development of fimepinostat, the first clinically evaluated agent exhibiting potent and balanced inhibition of both targets...From this comprehensive analysis, we outline key considerations and emerging design principles that may inform the next generation of PI3K/HDAC multitarget drug candidates. Insights derived from the diversity of chemical scaffolds, activity profiles, and selectivity patterns described herein may support the development of innovative therapeutic agents capable of overcoming current limitations in anticancer treatment."

Journal • Preclinical • Review • Oncology

A Phase 1 Trial of Fimepinostat in Children and Adolescents With Relapsed and Refractory Solid and CNS Tumors. (PubMed, Cancer Med) - P1 | "Fimepinostat was tolerable at a dose of 35 mg/m2 in children with relapsed and refractory solid and CNS tumors, but lacked significant clinical activity. Discovery of drugs to target Myc continues to be a high priority for childhood cancers."

Journal • P1 data • B Cell Lymphoma • Brain Cancer • Burkitt Lymphoma • CNS Tumor • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Neuroblastoma • Non-Hodgkin’s Lymphoma • Oncology • Pediatrics • Solid Tumor • MYCN

Dual PI3K and HDAC inhibitor, CUDC-907, effectively inhibits endometrial cancer growth in vitro and in vivo. (PubMed, Front Oncol) - "Our findings suggest that CUDC-907 is a promising agent that can re-sensitize tumors to progestin therapy and improve outcomes for EC patients. This study supports CUDC-907 as a potent treatment strategy in endometrial cancer and identifies IGF-1 as a potential surrogate serum biomarker for therapeutic response."

Journal • Preclinical • Endometrial Cancer • Genetic Disorders • Obesity • Oncology • Solid Tumor • CDKN1A • EIF4EBP1 • HER-2 • IGF1 • PGR

Trial of CUDC-907 in Children and Young Adults With Relapsed or Refractory Solid Tumors, CNS Tumors, or Lymphoma (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Oct 2025 ➔ Feb 2026 | Trial primary completion date: Oct 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • B Cell Lymphoma • Brain Cancer • CNS Tumor • Glioma • Hematological Malignancies • Lymphoma • Neuroblastoma • Oncology • Solid Tumor • MYC • MYCN

Identifying Novel Epigenetic Therapies for T-Cell Lymphomas By High Throughput Drug Screen (ASH 2024) - "Introduction : Epigenetic alterations are known to contribute to development of T-cell lymphomas (TCL), and numerous epigenetic modifiers have shown safety and clinical efficacy in TCL leading to FDA approval of three histone deacetylase inhibiters (vorinostat, romidepsin, and belinostat)...At the conclusion of this screen, we tested cytotoxicity of our most encouraging compound in combination with other top performing compounds.Results : We identified BI-847325, bortezomib, camptothecin, CUDC-907, and WAY-118959-A as the most encouraging cytotoxic compounds that are not currently being used clinically. We compared the top 5 compounds to 4 standard of care (SOC) cytotoxic drugs (belinostat, gemcitabine, romidepsin, and vincristine) that are used clinically...We tested cytotoxicity of camptothecin in combination with 5 compounds (belinostat, bortezomib, BI-847325, romidepsin, and vincristine) that also demonstrated cytotoxicity in the malignant T-cells with relative..."

Cutaneous T-cell Lymphoma • Gene Therapies • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • ANXA5

Dual HDAC and PI3K Inhibitor CUDC-907 Inhibits Growth of Pleural Mesothelioma: The Impact of Cisplatin Sensitivity and Myc Expression. (PubMed, Cells) - "Combining CUDC-907 with cisplatin further decreased cell growth even in cisplatin-resistant cells. The majority of PM cell models are sensitive to CUDC-907, which may be a potent therapeutic agent in PM."

Journal • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • BAP1 • MYC • PTEN

CUDC-907 inhibits osteosarcoma through upregulation of PTX3 and inhibition of PI3K-AKT signaling. (PubMed, Eur J Pharmacol) - "This study further demonstrated that CUDC-907 related endogenous upregulation of PTX3 promotes apoptosis of osteosarcoma cells by inhibiting the PI3K-AKT pathway, which in turn elucidated the potential mechanism of osteosarcoma inhibition by CUDC-907. In conclusion, CUDC-907 promote apoptosis in osteosarcoma cells by promoting PTX3 expression and thus inhibiting the PI3K-AKT pathway."

Journal • Neuroblastoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • PTX3

Establishing a screening platform on patient-derived organoids to identify effective agents to treat glioblastoma (EANO 2025) - "Crizotinib (pintertumoral = 0.0002, pintratumoral = 0.0255), Fimepinostat (pintertumoral < 0.0001, pintratumoral = 0.0006) and Sunitinib (pintertumoral < 0.0001, pintratumoral = 0.0092) resulted in significant inter- as well as intratumoral differences in response to treatment. Nilotinib (pintertumoral = 0.0009), Dasatinib (pintertumoral = 0.0046), Sorafenib (pintertumoral = 0.0096) and Rapamycin (pintertumoral < 0.0001) showed intertumoral heterogeneity only. Last but not least, Selumetinib (pintratumoral = 0.0001) triggered significant intratumoral differences... Our findings support the use of PDOs as a promising ex vivo platform to model inter- and intratumoral heterogeneity and assess drug response in GBM. This study serves as a proof of concept for integrating drug panel testing into PDO-based workflows, highlighting its potential value for molecular tumor board decision-making. The observed variability in treatment response across tumor regions and..."

Clinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

CUDC-907 exerts an inhibitory effect on non-small cell lung cancer associated with induction of mitotic catastrophe and downregulation of YAP/TAZ signaling. (PubMed, Chem Biol Interact) - "Additionally, CUDC-907 treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model. Taken together, this study revealed the cytotoxic effects of CUDC-907 and its underlying mechanism, which suggests that CUDC-907 may be an effective therapeutic approach for treating NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • CASP8 • CASP9 • CCNA2 • CCNB1 • CDC25C • CDK1 • CDKN1A • ERN1 • GNRP • MAPK8 • PARP1 • PLK1

Fimepinostat is a dual inhibitor of tumor and angiogenesis in glioblastoma and synergizes with temozolomide through suppressing MYC. (PubMed, Korean J Physiol Pharmacol) - "Mechanism studies confirmed that fimepinostat acts on glioblastoma cells through suppressing Akt/MYC. Our findings suggest that dual targeting of tumor and angiogenesis by fimepinostat may provide an alternative approach for anti-glioblastoma therapy."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL. (PubMed, Signal Transduct Target Ther) - "Furthermore, this compound's effectiveness and safety were confirmed in both MH/NRASG12D BCP-ALL mouse model and MB patient-derived xenograft (PDX) model, outperforming conventional therapies. These results support the therapeutic potential of dual-pathway inhibition in MEF2D fusion (+) BCP-ALL and suggest CUDC-907 as a promising candidate for precision treatment in fusion-driven leukemias with similar molecular dependencies."

IO biomarker • Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL9 • HDAC9 • HNRNPUL1 • MEF2D

Histone deacetylase inhibitors target DNA replication regulators and replication stress in Ewing sarcoma cells. (PubMed, Cancer Res Commun) - "In this study, we identified that multiple HDAC inhibitors, including fimepinostat, romidepsin and panobinostat, downregulate the levels of the RRM1, RRM2, CHK1, and WEE1 proteins in Ewing sarcoma cells, and impair DNA replication. Additionally, proteomic studies identified that HDAC inhibitors also downregulate the level of the BRD4 protein, a BET bromodomain protein that regulates both the transcriptional program of the EWS::FLI1 oncoprotein and DNA replication. Overall, these results provide novel insight into the molecular mechanisms by which HDAC inhibitors target cancer cells, regulate DNA replication, and inhibit the cellular response to DNA replication stress."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • BRD4 • CDT1 • CHEK1 • EWSR1 • FLI1 • MCM2 • RRM1 • RRM2

Fimepinostat, Combination HDAC and Pi3-kinase Inhibitor Tumor-Directed Therapy for Cushing Disease (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: University of California, Los Angeles | Not yet recruiting ➔ Recruiting | Trial completion date: Jan 2025 ➔ Jan 2029 | Trial primary completion date: Jan 2025 ➔ Jan 2029

Enrollment open • Trial completion date • Trial primary completion date • Cushing’s Disease

The dual HDAC/PI3K inhibitor CUDC-907 inhibits the growth and proliferation of MYC-driven Group 3 medulloblastoma. (PubMed, Cell Death Discov) - "Furthermore, when CUDC-907 was combined with chemotherapeutic drug cisplatin, G0/G1 phase blocking effect was further enhanced. CUDC-907 in combination with radiotherapy (RT) inhibited DNA damage repair and increased DNA damage. These findings indicate that CUDC-907, either as a monotherapy or in combination with chemoradiotherapy, represents a promising therapeutic strategy for MYC amplified G3 MB, potentially influencing future clinical trials targeting this patient population."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • CDKN1A • MYC

HIV Reactivation Potential Evaluated by RNA-Seq and DNA Methylation Following LRA Stimulation (CROI 2025) - "Purified CD4+ T cells were cultured in-vitro for 20h with two LRAs: fimepinostat (CUD) and Ingenol-3-angelate (PEP), left unstimulated (UNS) or cultured with PMA+ionomycin+IL2 as positive control (CTR)...Conclusions MultiOMIC analysis of CD4+ T cells upon LRA stimulation revealed molecular features associated with HIV inducibility. These features may shed light on mechanisms of latency reversal and could guide the selection of new and more effective LRAs."

Epigenetic controller • Human Immunodeficiency Virus • Infectious Disease • CD4 • IL2

Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities. (PubMed, Bioorg Med Chem) - "Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors."

Journal • Review • Oncology

Trial of CUDC-907 in Children and Young Adults with Relapsed or Refractory Solid Tumors, CNS Tumors, or Lymphoma (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Jan 2025 ➔ Jun 2025 | Trial primary completion date: Jan 2025 ➔ Jun 2025

Trial completion date • Trial primary completion date • B Cell Lymphoma • Brain Cancer • CNS Tumor • Glioma • Hematological Malignancies • Lymphoma • Neuroblastoma • Oncology • Solid Tumor • MYC • MYCN

Synergistic antitumor effect of MK-1775 and CUDC-907 against prostate cancer. (PubMed, Invest New Drugs) - "Notably, the combination of MK-1775 and CUDC-907 leads to significant antitumor effects in vivo. Our findings provide a strong basis for a promising combination strategy against prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • RRM1

Advances in pharmacological treatment of Cushing's disease. (PubMed, Zhong Nan Da Xue Xue Bao Yi Xue Ban) - "Currently, three categories of medications are commonly used: 1) Drugs targeting somatostatin and/or dopamine receptors to inhibit pituitary adrenocorticotropic hormone (ACTH) synthesis (e.g., pasireotide, cabergoline); 2) drugs targeting adrenal cortex-related receptors to suppress steroid synthesis (e.g., ketoconazole, metyrapone, mitotane, and osilodrostat); 3) drugs acting on glucocorticoid receptors (e.g., mifepristone). Research on pharmacological treatments for Cushing's disease is ongoing, with new drugs such as seliciclib, CRN04894, fimepinostat, vorinostat, and SPI-62 currently in phase II clinical trial. The development of novel drugs holds promise for more precise and effective treatment for Cushing's disease patients."

Journal • Review • Cardiovascular • Cushing’s Disease • Endocrine Disorders

TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas. (PubMed, Neuro Oncol) - "TRIM21 may represent a therapeutic target for tumors, and inhibiting TRIM21 could be a potential strategy for tumor treatment."

Journal • Oncology • Pituitary Gland Carcinoma • Targeted Protein Degradation • MAP2K1 • TRIM21

High throughput screening identified the activity of histone deacetylase inhibitors in patient-derived models of undifferentiated pleomorphic sarcoma (EORTC-NCI-AACR 2024) - "Of four HDAC inhibitors with the lowest average IC50 values (romidepsin, 1.3 nM; CUDC-907, 6.5 nM; panobinostat, 15.6 nM; and quisinostat, 26.2 nM), quisinostat exhibited the most promising synergistic effects with doxorubicin in vitro. In vivo investigations into the anti-tumour response of patient-derived xenograft models of UPS to quisinostat, alone or in combination with doxorubicin, are ongoing. ConclusionQuisinostat demonstrates potent anti-tumour activity in patient-derived models of UPS in vitro, with an enhanced response when doxorubicin is added."

Clinical • Epigenetic controller • Oncology • Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma