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

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

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

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."

Journal

Design, synthesis, and anti-cancer evaluation of the novel conjugate of gemcitabine's ProTide prodrug based on CD13. (PubMed, Bioorg Chem) - "In this study, we designed and synthesized a novel series of bestatin-gemcitabine's ProTide prodrug conjugates aimed at enhancing the antitumor efficacy of NUC1031. 5f demonstrates significant in vivo anti-tumor activity in 22Rv1 xenograft tumor models. Our findings indicate that 5f shows strong potential for further development as a candidate for the treatment of prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANPEP

Synthesis, biological and pharmacokinetic characterization of a novel leucine ureido derivative as a multi-target anticancer agent. (PubMed, RSC Adv) - "Moreover, synergistic anti-proliferation effects against tumor cells were found when used in combination with 5-Fluorouracil (5-FU)...The biological activity evaluation showed that compound 3 exhibited more potent in vitro anti-proliferative, anti-metastatic, anti-angiogenic activities than the positive control bestatin...In vivo pharmacokinetic study displayed that compound 3 was absorbed quickly after oral administration in rats and maintained in vivo for a long time, but exhibited poor oral bioavailability. Generally speaking, compound 3 is a promising lead for further development of more potent analogs as anticancer agents."

Journal • PK/PD data • Oncology

Discovery of New Nanomolar Selective IRAP Inhibitors. (PubMed, J Med Chem) - "A few series of inhibitors inspired either by angiotensin IV, one of IRAP substrates, or by bestatin a pan aminopeptidase inhibitor, have been disclosed...Several inhibitors in the series displayed IRAP-dependent inhibition of antigen cross-presentation. These results pave the way to the development of novel therapeutic agents targeting IRAP."

Journal

Synthesis and biological evaluation of new dual APN/NEP inhibitors as potent analgesics. (PubMed, Bioorg Chem) - "In in-vivo antinociceptive assays, SDUY816 and SDUY817 demonstrated superior analgesic efficacy compared to Thiorphan and Bestatin in mice models of acute, inflammatory and neuropathic pains with jumping latencies exceeding 100 s and withdrawal thresholds more than 0.13 g...In addition, SDUY816 and SDUY817 exerted the analgesic activity in a concentration- and time-dependent manner with SDUY816 possessing acceptable pharmacokinetic properties (t1/2 = 4.02 h and F = 27 %) and low toxicity. These findings provide alternative analgesic therapeutics that are potentially devoid of opioid-associated side effects."

Journal • Addiction (Opioid and Alcohol) • Neuralgia • Pain • PENK

Delta-Fly Pharma Inc.: Progress Update of the Phase III Clinical Trial of DFP-14323 (Businesswire) - "...We are pleased to announce that Afatinib, which is being treated with DFP-14323 in our ongoing Phase III clinical trial, has been approved by the Japanese Lung Cancer Society in its 'Lung Cancer Treatment Guidelines 2024' (issued on October 20, 2024) as a first-line treatment for EGFR mutation-positive (uncommon mutation) non-small cell lung cancer (NSCLC), with a stronger recommendation than Osimertinib.The development of DFP-14323 is being conducted in patients (stage III/IV) with epidermal growth factor receptor (EGFR) mutation-positive uncommon mutation NSCLC in a Phase III clinical trial (superiority study) comparing DFP-14323 in combination with Afatinib (20 mg/day) and Afatinib (40 mg/day) alone. The strongly recommended treatment with afatinib as first-line therapy must accelerate the enrollment of NSCLC patients through this trial."

Clinical guideline • Non Small Cell Lung Cancer

Why Bestatin Prefers Human Carnosinase 2 (CN2) to Human Carnosinase 1 (CN1). (PubMed, J Phys Chem B) - "In contrast, the high mobility of the aryl end and the complete loss of metal-BES interactions in CN1 cause a loose BES binding. Seemingly, polar termini were required for a good CN1 inhibitor."

Journal

The triple combination DBDx alleviates cytokine storm and related lung injury. (PubMed, Int Immunopharmacol) - "Here, we investigated the anti-cytokine storm efficacy of DBDx, a triple drug combination composed of dipyridamole, ubenimex and dexamethasone. All of these results demonstrate that DBDx, a triple combination of clinical orally-administered drugs, can alleviate cytokine storm and related lung injury. DBDx is beneficial for treating cytokine storm disorders."

Cytokine storm • Journal • Respiratory Diseases • HIF1A • IL1B • IL6 • TLR4 • TNFA

Curcumin suppresses colorectal tumorigenesis through restoring the gut microbiota and metabolites. (PubMed, BMC Cancer) - "The gut microecological balance was disrupted in AOM/DSS-induced CRC mice, accompanied by metabolite dysbiosis. Curcumin restored the equilibrium of the microbiota and regulated metabolites, highly indicating that curcumin may alleviate the development of AOM/DSS induced colorectal cancer in mice by regulating intestinal flora homeostasis and intestinal metabolites."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Metabolic Disorders • Oncology • Solid Tumor

A Nanofluorescent Probe for Evaluating the Fluctuation of Aminopeptidase N in Nonalcoholic Fatty Liver Disease and Hepatic Fibrosis. (PubMed, Anal Chem) - "Furthermore, we investigated the inhibitory effect of the APN inhibitor bestatin in nonalcoholic fatty liver and hepatic fibrosis disease models, confirming its regulatory effect on APN levels in cells and in vivo in both disease models. Therefore, this study may offer diagnostic possibilities for detecting NAFLD and hepatic fibrosis."

Journal • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatotic Liver Disease • ANPEP

Effect of X-ray irradiation on renal excretion of bestatin through down-regulating organic anion transporters via the vitamin D receptor in rats. (PubMed, Chem Biol Interact) - "Additionally, elevated plasma urea nitrogen levels and histopathological changes were observed in rats after exposure to irradiation. The "RT-PK" phenomenon of bestatin occurs in rats after exposure to irradiation, possibly resulting in the regulation of the expressions and activities of renal Oats via activation of the Vdr signalling pathway."

Journal • Preclinical • VDR

Delta-Fly Pharma Inc.: Notice of initiation of patients enrollment in Phase III Pivotal comparative clinical trial of DFP-14323 (Businesswire) - "We are pleased to announce that the enrollment of patients in the Phase III clinical trial of DFP-14323 in combination with Afatinib (20 mg/day) versus Afatinib (40 mg/day) alone in stage III/IV non-small cell lung cancer patients with uncommon EGFR mutation positive that was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Feb. 2024, has started as of today in Japan. This Phase III clinical trial will be conducted at 30 sites with NSCLC experts in Japan and the superiority of the add-on effect of DFP-14323 on progression-free survival (PFS) as primary endpoint will be confirmed."

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

State of the Art in the Development of Human Serum Carnosinase Inhibitors. (PubMed, Molecules) - "Bestatin is the only inhibitor reported other than carnostatine, although its activity is not selective towards serum carnosinase. Herein, we present a review of the most critical findings on human serum carnosinase, including enzyme expression, localization and substrate selectivity, along with factors affecting the hydrolytic activity, its implication in human diseases and the properties of known inhibitors of the enzyme."

Journal • Review • CNS Disorders • Diabetic Nephropathy • Genetic Disorders • Nephrology • Renal Disease