ubenimex (DFP-14323) / Delta-Fly Pharma - LARVOL DELTA

A phase II study of DFP-14323, a non-specific immunomodulator, in combination with low-dose afatinib as first-line therapy for common EGFR mutation-positive NSCLC. (PubMed, Ther Adv Med Oncol) - "The combination of DFP-14323 and low-dose afatinib was considered to have the potential for future clinical utility for EGFR mutation-positive NSCLC. As the next step, a study evaluating this combination therapy in uncommon EGFR mutation-positive NSCLC is currently underway in Japan (jRCT2061230111)."

Journal • P2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Interstitial Lung Disease • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • ANPEP • EGFR

Bestatin inhibits the development of cutaneous melanoma by inhibiting the expression of LTA4H. (PubMed, Front Immunol) - "In this study, MR analysis revealed that high expression of LTA4H can promote the occurrence of CM. In addition, the results of the cell experiments revealed that bestatin can inhibit the development of melanoma cells by reducing the expression of LTA4H."

Journal • Cutaneous Melanoma • Gene Therapies • Melanoma • Oncology • Solid Tumor • LTA4H

Tumor microenvironment improved by nanostructured lipid carriers co-deliverying paclitaxel and ubenimex to treat breast cancer. (PubMed, Drug Dev Ind Pharm) - "Consequently, the PTX/Uben-NLC alleviated TME immunosuppression and enhanced anti-breast-cancer activity. Dual-drug-loaded nanostructured lipid carriers alleviated TME immunosuppression to enhance synergistic anti-breast cancer therapy and provided a feasible solution for breast cancer treatment."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • IFNG • IL10 • IL12A • TGFB1 • TNFA

Host-directed treatments for tuberculous meningitis utilizing a multi-platform approach across mouse and human models. (PubMed, Nat Commun) - "Imatinib, bestatin, roflumilast, palacaparib, thalidomide/pomalidomide and semaglutide outperform the current standard of care by reducing mortality and/or neurological deficits in mice via suppression of neuroinflammation. Importantly, these HDTs significantly reduce microglial activation in Mycobacterium tuberculosis-infected human brain organoids and attenuate proinflammatory cytokines, particularly IFNγ within CD4+ T-cells in patient-derived PBMCs. These findings highlight the potential of targeted HDTs to improve outcomes in TB meningitis and warrant clinical investigation."

Journal • Preclinical • CNS Disorders • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD4 • IFNG

Harnessing tumor-associated exosomal aminopeptidase N as a dual-function tool for monitoring and tackling chemoresistance in gastric cancer. (PubMed, Cell Commun Signal) - "Functional validation demonstrated that APN depletion via shRNA or CRISPR restored cisplatin sensitivity in refractory cells, whereas APN overexpression conferred chemoprotection. A neutralizing anti-APN monoclonal antibody resensitized resistant cells and showed superior efficacy compared with the broad-spectrum peptidase inhibitor bestatin in vivo...Clinically, serum exosomal APN levels robustly distinguished progressive disease from disease control in a cohort of 105 patients (AUC = 0.85; optimal cutoff 0.936 ng/mL). Collectively, these findings position exosomal APN as a dual-function tool, serving both as a dynamic liquid biopsy biomarker and an antibody-targetable node for monitoring and overcoming chemoresistance in gastric cancer."

Journal • Gastric Cancer • Oncology • Solid Tumor • AKR1C2 • ANPEP

CNDP2 drives renal tubular fibrosis in diabetic kidney disease via a sulfur-containing amino acids-mTOR signaling axis. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "CNDP2 drives renal tubular fibrosis in DKD by activating mTOR signaling through disruption of SAAs metabolism. Our findings reveal a novel "CNDP2-SAAs-mTOR" pathway, identifying CNDP2 as a promising therapeutic target for DKD intervention."

Journal • Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Immunology • Nephrology • Renal Disease

A phase II study of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin for previously untreated advanced squamous non–small cell lung cancer: TORG2241(UBE-Q). (ASCO 2026) - P2 | "Ubenimex with 120 mg/day (60 mg twice daily) combined with pembrolizumab, nab-paclitaxel, and carboplatin was feasible and showed encouraging antitumor activity with manageable safety in previously untreated advanced squamous NSCLC, supporting further randomized evaluation."

Metastases • P2 data • Febrile Neutropenia • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • ANPEP

APN Inhibitor Bestatin Induces MM Cell Differentiation Through the CD79B/BTK/STAT3 Pathway. (PubMed, Cells) - "Furthermore, both the CD79B/BTK inhibitor Ibrutinib and the STAT3 agonist GCDA potentiated the cytotoxicity of the clinical MM drug Ixazomib. In summary, our findings establish that the APN inhibitor Bestatin induces MM cell differentiation via the CD79B/BTK-STAT3 signaling axis. Targeting this pathway represents a promising strategy to enhance the efficacy of Ixazomib, providing a compelling rationale for novel combination therapies in MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • CD79B • IL6 • ITGA5

NAALADL1 modulates cellular resistance to Tumor Treating Fields in colorectal cancer. (PubMed, NPJ Precis Oncol) - "Virtual screening further identified Lumacaftor and Bestatin as candidate NAALADL1 inhibitors, which synergized with TTFields to suppress CRC cell growth. These findings highlight significant heterogeneity in CRC cell line responses to TTFields and identify NAALADL1 as a key modulator of resistance, suggesting its potential as a target for improving TTFields-based therapies in CRC."

Journal • Brain Cancer • Colorectal Cancer • Glioblastoma • Oncology • Solid Tumor • FOLH1

RETRACTION: Ubenimex Reverses MDR in Gastric Cancer Cells by Activating Caspase-3-Mediated Apoptosis and Suppressing the Expression of Membrane Transport Proteins. (PubMed, Biomed Res Int) - No abstract available

Journal • Gastric Cancer • Oncology • Solid Tumor • CASP3

In vitro investigation of the proliferative and metastatic role of CD13 in cancer (AACR 2025) - "An example is the aminopeptidase inhibitor, Ubenimex (Bestatin), which has been approved in Japan as an adjuvant to chemotherapy for acute non-lymphocytic leukemia...Oncol Rep. 2016; 35(4):2121-30."

Metastases • Preclinical • Acute Myelogenous Leukemia • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioblastoma • Glioma • Hematological Malignancies • Leukemia • Neuroblastoma • Oncology • Prostate Cancer • Solid Tumor • ANPEP • STAT3

Uncovering the Role of Dimerization on Dynamics and Inhibitor Stability in Human vs. Xenopus LTA4H. (PubMed, Biophys J) - "We investigate the conformational stability and binding of the inhibitor bestatin to Xenopus laevis LTA4H (xlLTA4H) in both monomeric and dimeric states using all-atom molecular dynamics (MD) simulations...These results indicate that dimerization in xlLTA4H may reduce ligand binding stability, despite the ligand maintaining a consistent binding pose in the crystal structure. Our findings highlight the complex interplay between protein oligomerization, dynamic networks, and inhibitor binding, underscoring the importance of considering physiological conditions and dynamic behavior beyond static structural data in drug design for LTA4H."

Journal • LTA4H

Ubenimex synergizes with the PD-L1 blockade in gastric cancer by competitively binding LAP3 with UBE3A. (PubMed, Cell Death Dis) - "This mechanism reinvigorates CD8+ T cell infiltration and cytotoxic activity within the TME, thereby overcoming resistance to anti-PD-L1 therapy. In conclusion, our study provides a strong rationale for the synergistic potential of Ubenimex in combination with PD-1/PD-L1 blockade, offering a promising strategy to overcome current limitations of ICIs therapy in GC patients."

IO biomarker • Journal • Gastric Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CD8 • UBE3A

The role and mechanism of exosomal aminopeptidase n (APN/CD13)-mediated CTL cell dysfunction in aplastic anemia (ASH 2025) - "In vitro functional assays (CCK-8 and flow cytometry) evaluated theeffects of CD13 and its inhibitor bestatin on CTL proliferation and inflammatory cytokine (TNF-α/IFN-γ)secretion...The CD13 inhibitor can counteract this effect,potentially offering therapeutic benefits for the disease. Our findings may contribute to the identificationof novel potential biomarkers for SAA, and could provide valuable insights for developing therapeutic orpersonalized treatment strategies for SAA."

Anemia • Aplastic Anemia • Immunology • Myelodysplastic Syndrome • ANPEP • CD4 • CD73 • CD8 • GPRC5C • IFNG • NT5E • SAA2 • TINCR • TNFA

Identification of KKL-35 as a Novel Carnosine Dipeptidase 2 (CNDP2) Inhibitor by In Silico Screening. (PubMed, Molecules) - "Although bestatin (BES) has been identified as a CNDP2 inhibitor, its limited specificity and suboptimal drug-like properties have limited its therapeutic potential...This positions it as an attractive and tractable starting point for lead optimization. Taken together, these findings establish KKL-35 as a validated CNDP2 inhibitor and a promising lead compound for the development of more selective therapeutics targeting CNDP2-mediated cancer cell metabolism."

Journal • Oncology

Dopaminergic and Opioid Systems Interact to Produce Peripheral Antinociception in Mice. (PubMed, J Integr Neurosci) - "Overall, the data suggest that opioid-mediated antinociception depends on the activation of the dopaminergic system. This demonstrates that pain modulation can be enhanced through the interaction of these systems. Controlling pain at a peripheral level by activating endogenous pathways could be a promising approach to pain management."

Journal • Preclinical • Pain

Soluble CD13 engages protease-activated receptor 4 to promote synovial inflammation and angiogenesis in rheumatoid arthritis (ACR Convergence 2025) - "We identified PAR4 as a second functional sCD13 receptor that mediates proinflammatory signaling in RA FLS and angiogenic responses in endothelial cells, which positions PAR4 as a therapeutic target in RA."

Immunology • Inflammation • Inflammatory Arthritis • Osteoarthritis • Rheumatoid Arthritis • Rheumatology • ANPEP • IL1B • TNFA

Cannabidiol engages the peripheral endogenous opioid system to produce analgesia in neuropathic mice. (PubMed, Neurosci Lett) - "Bestatin (400 µg/paw), a selective aminopeptidase-N inhibitor, potentiates the intermediate analgesic response of CBD at the dose of 2 mg/Kg...CTOP (5, 10, and 20 µg/paw) and naltrindole (30, 60, and 120 µg/paw), μ and Δ opioid receptor antagonists, but not norBNI (200 µg/paw), a κ opioid receptor antagonist, partially reversed the CBD analgesia. Thus, our study shows that cannabidiol may induce activation of opioid receptors in the periphery as a part of its analgesic mechanism in neuropathic pain."

Journal • Preclinical • CNS Disorders • Epilepsy • Neuralgia • Pain • Psychiatry

Aminopeptidase N: a multifunctional and promising target in medicinal chemistry. (PubMed, RSC Adv) - "Some of them, such as bestatin or tosedostat, have already been tested as therapeutics with partial success. This article aims to bring an overview of multiple APN functions and implications for various diseases and their inhibitors which have already been prepared, and to suggest areas where the development of inhibitors may be promising in the future."

Journal • Review • Dermatitis • Infectious Disease • Inflammation • Novel Coronavirus Disease • Oncology

Early evaluation of anti-angiogenic effects with gadolinium(III) labeled APN/CD13 specific binding peptides magnetic resonance imaging. (PubMed, Sci Rep) - "Magnetic resonance imaging was conducted via intraperitoneal injection of labeled probes and Gd-DOTA, both before and after treatment with ubenimex at a dose of 0.5 mg/kg/day for seven consecutive days...Following treatment, the T/NT ratio of the HT-1080 transplanted tumors was significantly reduced (P < 0.001, n = 5), accompanied by a notable decrease in CD13 expression and negligible changes in the sum of the long and short diameters (P = 0.39, n = 5). The research findings revealed that Gd-DOTA-G3CNGRC can serve as a highly specific gadolinium-based magnetic resonance imaging probe for monitoring the efficacy of anti-angiogenic therapy."

Journal • Oncology • Transplantation • ANPEP

Role of bestatin as a treatment for periodontitis. (PubMed, Front Dent Med) - "The current review highlights Bestatin as a promising therapeutic representative for periodontitis, where it is involved in inhibiting modulating biofilms, reducing tissue destruction, and P. gingivalis, in preclinical studies. Compared to traditional therapies, bestatin provides unique advantages, non-cytotoxicity, including specificity, and dual action against microbial dysbiosis along with biofilm-associated resistance."

Journal • Review • Dental Disorders • Infectious Disease • Inflammation • Periodontitis

High-Altitude-Induced Cerebral Edema in Mice is alleviated by Bestatin-Mediated Blood-Brain Barrier Protection. (PubMed, J Neurophysiol) - " Acute HH-induced upregulation of CD13 primarily damages the BBB by enhancing MMP-9 expression and microglial activation, leading to vasogenic edema. And bestatin, by inhibiting CD13, has the ability to reduce cerebral edema and neurological deficits, showing potential as a future HACE prevention and treatment."

Journal • Preclinical • Oncology • ANPEP • HIF1A • MMP9

Genome-Wide Identification and Expression Profiling of Glycosidases, Lipases, and Proteases from Invasive Asian Palm Weevil, Rhynchophorus ferrugineus. (PubMed, Insects) - "In silico analysis revealed that the selected enzymes exhibited similar ligand-binding affinity to their corresponding substrate, except for protease aminopeptidase N, RferPro40, which exhibited poorer affinity to the inhibitor bestatin. Overall, our study serves as a foundation for further functional analysis and offers a novel target for the development of a novel bio-rational insecticide for R. ferrugineus."

Journal • Targeted Protein Degradation

Design and synthesis of novel sulfanilamide derivatives as aminopeptidase N inhibitors. (PubMed, Bioorg Med Chem Lett) - "Among the series, compound 2k exhibited the inhibitory activity (IC50 = 4.3 μM) as effectively as a positive control drug Bestatin...These results validated simultaneously occupying S1' and S2' pockets as a viable design strategy for discovering APN inhibitors with a non-canonical binding modality. We anticipate that compound 2k with high selectivity will be harnessed as a structurally distinctive probe candidate to investigate the pathophysiological roles of APN in tumor angiogenesis and metastasis."

Journal • Oncology • MMP2

Biochemical characterization and modulation by abscisic acid of aminopeptidase-N activity in the digestive tract of Dentudo Oligosarcus jenynsii from Mar Chiquita coastal lagoon (Buenos Aires, Argentina). (PubMed, J Fish Biol) - "Bestatin inhibited the activity in the intestine in both stages, but it had no effect on the liver...The presence of ABA in vitro decreased APN activity in both intestine and liver from juveniles. These results suggest the presence of APN in both juveniles and adults, as well as its differential modulation by ABA in juveniles."

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