sirpiglenastat (DRP-104) / Dracen Pharma - LARVOL DELTA

Targeting DCLK1-mediated glutamine addiction in chemoresistant ovarian cancer (AACR 2025) - "Targeted gene expression profiling and pathway analysis revealed DCLK1 inhibition in cisplatin resistant (CPR) OC spheroids upregulated genes involved in glutamine metabolism. Collectively, our findings establish DCLK1 as a key regulator of metastasis and demonstrate that its inhibition induces glutamine dependency in chemoresistant tumor cells. Thus, the combined use of DCLK1 inhibitors (e.g., DCLK1-IN-1) with glutamine metabolism inhibitors (e.g., DRP-104) represents a rational therapeutic approach to mitigate peritoneal metastases in a chemoresistant setting."

Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor

Cyanobacteria-derived RNA aptamer supports prostate cancer hormone sensitivity (AACR 2025) - "On the other hand, non-metabolizable L-Gln analogues like 6-Diazo-5-oxo-l-norleucine (DON) and DRP104 have shown promising antitumor effects...The L-Gln-depleting aptamer, with demonstrated serum stability, limited the proliferation, and lineage plasticity of the castrate resistant prostate tumors alone and in combination therapy with AR antagonists, enzalutamide and apalutamide in subcutaneous and orthotopic mouse models...Superiority of the functionalized nanoparticle targeting was demonstrated in an orthotopic PCa model over the un-targeted aptamer in reducing tumor weight. The studies demonstrated elevated L-Gln can be necessary and sufficient for castrate resistance, as its depletion sensitizes prostatic tumors to AR inhibition."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FGF8 • FOXM1

Metabolic profiling of MEKi-treated fusion-negative rhabdomyosarcoma cell lines suggests a role for glutamine antagonism as a preclinical therapeutic approach (AACR 2025) - "We investigated the effects of DRP-104 on markers of tumor growth, DNA damage, and cell death by western blotting. As our own and other data support a role for MEKi and glutamine antagonism in RAS-active tumor models [5], future investigations will seek to combine DRP-104 with trametinib in cell-based and in vivo RAS-RMS models."

Preclinical • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FGFR1 • PAX3 • PAX7

Resilience and vulnerabilities of tumor cells under purine shortage stress. (PubMed, bioRxiv) - "While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities."

Journal • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioma • Oncology • Prostate Cancer • Solid Tumor • MTAP

DRP-104 (Glutamine Antagonist) in Combination With Durvalumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1/2 | N=27 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Aug 2029 ➔ Sep 2033

Trial completion date • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

Addressing Clinical Limitations of Glutaminase Inhibitors: Novel Strategies for Osimertinib-Resistant Lung Cancer by Exploiting Glutamine Metabolic Dependency. (PubMed, Adv Sci (Weinh)) - "This prodrug demonstrates superior safety compared to natural DON and greater antitumor activity against resistant tumors compared to the clinical phase II drug DRP104. These findings may address the clinical limitations of GLS1 allosteric inhibitors and underscore prodrug strategies in effectively treating Osimertinib-resistant lung cancer, providing a foundation for future clinical trials."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NQO1 • SLC1A5

DRP-104 (Glutamine Antagonist) in Combination With Durvalumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1/2 | N=27 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Feb 2027 ➔ Aug 2029 | Trial primary completion date: Feb 2027 ➔ Aug 2028

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

Exploiting a critical vulnerability to glutamine antimetabolite therapy in fibrolamellar hepatocellular carcinoma (FLC) (CRI-ENCI-AACR ICIC 2024) - P1/2 | "Our preliminary data using preclinical models of FLC and human biospecimens from FLC patients shows that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor cell characterized by glutamine dependence...Furthermore, the combination of JHU-083, a glutamine antagonist, in combination with checkpoint inhibitor therapy dramatically improved antitumor effects and enhanced survival in a preclinical model of FLC...Patients will receive DRP-104 (145 mg s.c. twice weekly) in combination with a fixed dose of durvalumab (1500 mg i.v. every 28 days)...Secondary objectives include progression free survival (PFS), overall survival (OS), and immunological correlates (NCT06027086). Through this trial, we will test the hypothesis that glutamine antagonism in FLC reverses resistance to immune checkpoint inhibitor (ICI) therapy through modulating the TiME."

CNS Disorders • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Disorders • Oncology • Psychiatry • Solid Tumor • DNAJB1 • PRKACA

A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death. (PubMed, Cancer Lett) - "Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • GPX4

Unveiling therapeutic frontiers: DON/DRP-104 as innovative Plasma kallikrein inhibitors against carcinoma-associated hereditary angioedema shocks - a comprehensive molecular dynamics exploration. (PubMed, Cell Biochem Biophys) - "Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • Oncology • Pain

DRP-104 with durvalumab in fibrolamellar hepatocellular carcinoma (YouTube) - "Marina Baretti, MD...gives an overview of a new Phase I/II trial (NCT06027086) using DRP-104 with durvalumab to treat fibrolamellar hepatocellular carcinoma (FLC)."

Video

Glutamine antagonists may KEAP lung cancer in check. (PubMed, Sci Adv) - "The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers."

Journal • Review • Lung Cancer • Oncology • Solid Tumor • KEAP1 • NFE2L2

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer. (PubMed, Sci Adv) - "Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer."

Checkpoint block • Checkpoint inhibition • IO biomarker • Journal • Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • KEAP1

Orphan Designation: Treatment of Hepatocellular Carcinoma (FDA) - Date Designated: 02/20/2024

Orphan drug • Hepatocellular Cancer

Glutamine antagonist clinical trial - introduction and overview (YouTube) - "This brief video featuring Mark Yarchoan, MD and Marina Baretti, MD of John Hopkins University describes the rationale and structure of a new clinical trial of a glutamine antagonist (DRP-104) in combination with Durvalumab for fibrolamellar patients."

Video

DRP-104 (Glutamine Antagonist) in Combination With Durvalumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1/2 | N=27 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Metastases • Phase classification • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

DRP-104 (Glutamine Antagonist) in Combination With Durvalumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1/2 | N=27 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

DON/DRP-104 as potent serine protease inhibitors implicated in SARS-CoV-2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach. (PubMed, J Cell Biochem) - "We performed comparative studies on DON and DRP-104 against a clinically potent TMPRSS2 inhibitor, nafamostat, and a standard serine protease inhibitor, 4-(2-Aminoethyl) benzenesulfonyl fluoride (AEBSF) against TMPRSS2 and found improved TMPRSS2 inhibition through synergistic binding of the S1/S1' subdomains. Intriguingly, while both DON and DRP-104 showed similar loop transition patterns, DRP-104 preserved loop structural integrity. As evident from our systematic comparative study using experimentally/clinically validated inhibitors, DRP-104 may serve as a potent and novel TMPRSS2 inhibitor and warrants further clinical investigation."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Glutamine antagonist DRP-104 in combination with durvalumab in patients with advanced fibrolamellar carcinoma (FLC) following progression on prior anti-PD(L)1 therapy. (ASCO-GI 2024) - P1b/2 | "Preclinical work from our laboratory and others has revealed that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor characterized by glutamine dependence. This study has been registered under NCT06027086 and is expected to begin enrollment in December 2023. Clinical trial information: NCT06027086."

Clinical • Combination therapy • Metastases • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • DNAJB1 • PRKACA

DRP-104 (Glutamine Antagonist) in Combination With Durvalumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1/2 | N=27 | Not yet recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

New P1/2 trial • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

DON of Hope: Starving Pancreatic Cancer by Glutamine Antagonism. (PubMed, Cancer Res) - "Traditional attempts using glutamine inhibitors like 6-diazo-5-oxo-L-norleucine (DON) and CB-839 were unsuccessful, but new hope arises with DRP-104, a pro-drug of DON...In a recent study published in Nature Cancer, Encarnación-Rosado and colleagues demonstrated in pre-clinical models that pancreatic ductal adenocarcinoma (PDAC) responds well to DRP-104, though tumors adapt through the MEK/ERK signaling pathway, which can be countered by the MEK inhibitor trametinib...Both studies underscore the potential of inhibiting glutamine metabolism and adaptive pathways as a promising strategy against PDAC. These findings pave the way for upcoming clinical trials utilizing DRP-104 and similar glutamine antagonists in the battle against solid tumors."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer. (PubMed, Prostate) - "The prodrug DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Discovery of tert-Butyl Ester Based 6-Diazo-5-oxo-l-norleucine Prodrugs for Enhanced Metabolic Stability and Tumor Delivery. (PubMed, J Med Chem) - "Of these, P11, tert-butyl-(S)-6-diazo-2-((S)-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes."

Journal • Gastrointestinal Disorder • Oncology

Newfound Mechanism Suggests Drug Combination Could Starve Pancreatic Cancer (PRNewswire) - "In the current study, DRP-104 treatment alone decreased PDAC growth in mouse models of pancreatic cancer. Importantly, the current team also found that PDAC cells pushed into metabolic crisis by DRP-104 increase signaling through a protein called extracellular signal-regulated kinase or ERK, to make up for their loss of glutamine metabolism. When the team combined DRP-104 with an existing drug that blocks the ERK signaling pathway, trametinib, it further improved survival in pancreatic cancer mouse models compared to DRP-104 treatment alone."

Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Targeting pancreatic cancer metabolic dependencies through glutamine antagonism. (PubMed, Nat Cancer) - "Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor