pidnarulex (CX-5461) / Senhwa Biosci - LARVOL DELTA

The ribosome biogenesis inhibitor CX-5461 increases platelet count in humans and enhances murine megakaryopoiesis (ASH 2025) - "CX-5461 treatment reduced the depth of carboplatin-induced thrombocytopenia and accelerated platelet recovery. RNA-Polymerase I inhibition offer a novel target for treating thrombocytopenia and a tool tofurther our understanding of thrombopoiesis. This unique property distinguishes CX-5461, and otherinhibitors of RNA Pol I transcription from other anticancer agents and highlights this class of reagent tohave potential dual utility as both antineoplastic and thrombopoietic agents, particularly in settings ofchemotherapy-induced thrombocytopenia or in patients with impaired TPO signalling."

Preclinical • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Thrombocytopenia

Acute myeloid leukemias with UBTF tandem duplications respond to combined BCL-2 and RNA polymerase I inhibition with increased stemness and a quiescent-like state (ASH 2025) - "Following engraftment, mice were treated with vehicle,CX-5461, venetoclax plus azacitidine (VEN-AZA), or the combination of CX-5461 and VEN-AZA. Further analyses to investigate the functional consequences of this pronounced primitiveshift upon CX-5461 treatment are currently underway.In conclusion, our findings demonstrate that VEN-AZA in combination with CX-5461 reduces tumorburden in preclinical models and induces a pronounced shift toward a primitive, quiescent, stem-likephenotype in UBTF-TD AML, reflecting significant cellular plasticity. These data support combinedtargeting of BCL-2 and RNA polymerase I as a promising therapeutic strategy for AML patients harboringUBTF-TD."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2 • CD34 • FLT3 • NPM1 • TNFA • WT1

Senhwa Biosciences and BeOne Medicines Announces a Clinical Supply Agreement to Address the Challenge of Cold Tumors (PRNewswire) - "This agreement will supply a global, multi-center Phase 1b/2a clinical trial to evaluate Senhwa's lead compound Pidnarulex (CX-5461) in combination with BeOne's tislelizumab, a PD-1 inhibitor, in patients with advanced solid tumors, including pancreatic ductal adenocarcinoma (PDAC) and immune checkpoint inhibitor (ICI)-refractory melanoma....The study will enroll patients at multiple sites in the United States and Taiwan, assessing safety, tolerability, and preliminary efficacy of the CX-5461 plus tislelizumab combination."

Commercial • New P1/2 trial • Melanoma • Pancreatic Ductal Adenocarcinoma

Dual RNA Polymerase I Inhibition with CX-5461 and BMH-21 Synergizes in Breast Cancer by Activating p53-Dependent Stress. (PubMed, bioRxiv) - "Collectively, our findings demonstrate that CX-5461 and BMH-21 are complementary in inhibiting Pol I, activating p53, and suppressing cancer cell growth. Based on these pre-clinical findings, dual Pol I inhibition with CX-5461 and BMH-21 represents a promising therapeutic strategy for treating cancer that is potentially both broadly applicable and tolerable."

Journal • Breast Cancer • Oncology • Solid Tumor

Reply to: The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells. (PubMed, medRxiv) - P1 | "This is particularly important given that several clinical trials, including a Phase Ib study of CX-5461 in patients with solid tumours [ NCT04890613 ] and a National Cancer Institute sponsored Phase I trial [ NCT06606990 ] are currently enrolling patients. These ongoing and planned clinical efforts highlight both the therapeutic promise of CX-5461 and the importance of evaluating this agent within rigorous and clinically relevant frameworks."

Journal • Tumor mutational burden • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • TMB

Targeting RNA polymerase I to boost natural killer cell anticancer activity in multiple myeloma. (PubMed, Cell Death Dis) - "Our study examined two "first-in-class" RNA Pol I inhibitors, CX-5461 and BMH-21, which differentially regulate NK cell-activating and inhibitory ligand expression in MM. This effect was modulated by Lenalidomide and Panobinostat. Moreover, RNA Pol I inhibition enhanced Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC) of NK cells against MM, uncovering novel immuno-mediated antitumor mechanisms."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • HLA-E • IFNG • TNFA

Impaired rRNA Synthesis Contributes to BCL-2 Induced Chemoresistance in Diffuse Large B-Cell Lymphoma (ASH 2024) - "In this study we first confirmed that the standard CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy induces a potent ribosome biogenesis inhibition in DLBCL cell lines by hindering rRNA synthesis, as assessed by 45s rRNA qPCR. This activity was mainly attributable to doxorubicin, which mirrored the effects of well-known RiBi inhibitors (actinomycin D and CX-5461) on rRNA transcription...In line with this, combinatory strategies aimed at boosting p53 activation, proved to be effective in vitro in BCL-2 overexpressing DLBCL cells and in vivo in BCL-2 positive patient-derived xenograft models, synergizing with venetoclax. In fact, combinations of RiBi inhibitors with drugs stabilizing p53 in a RiBi-independent manner, such as MDM2i or etoposide, restored efficient p53 stabilization in BCL-2 overexpressing DLBCL models...Furthermore, nucleolar area was an independent prognostic predictor in multivariate analysis, outperforming BCL-2 mRNA levels...."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Purine Metabolism Modulates Leukemia Stem Cell Maintenance in MLL-Rearranged Acute Leukemia (ASH 2023) - "We utilized genetic and pharmacological (mycophenolate mofetil, MMF, a purine biosynthesis inhibitor of IMPDH) approaches to target the enhanced purine metabolism and found inhibition of the purine synthesis pathway promotes myeloid differentiation of both murine and human LSCs...Moreover, we found that the myeloid differentiation induced by MMF or CX-5461 is associated with reduced chromatin occupancy of the MLL-AF9 complex, especially Menin, and downregulated expression of MLL-AF9 target genes, such as Meis1, Hoxa9, and Myc, suggesting a regulatory role of nucleolar rRNA transcription on MLL-AF9 oncogenic gene expression program...Altogether, our findings reveal that purine metabolism maintains nucleolar rRNA transcription homeostasis to modulate MLL fusion complex-induced leukemogenic transcriptional activity in LSCs. The enhanced purine metabolism emerges as a crucial dependency for LSCs, providing potential targets for novel therapeutic strategies in treating..."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • HOXA9 • KMT2A • MEIS1

Pre-rRNAs control mitosis by maintaining chromosomal segregation through protecting SMC2 from AURKA-mediated phosphorylation. (PubMed, Cell Death Dis) - "The AURKA-binding proteins on the chromosome were determined by immunoprecipitation and mass-spectrometry after cells were treated with Act D, BMH-21 or CX5461, respectively, and the chromosomal segregation controlling proteins were selected...The phosphorylation deficient Flag-SMC2 T574A reverses the mitotic catastrophe caused by Pol I inhibition. Collectively, we demonstrate that pre-rRNAs protect SMC2 from the AURKA-mediated phosphorylation to maintain normal mitosis."

Journal

Targeting treatment-resistant Systemic Lupus Erythematosus through transcriptome-informed drug repurposing (ACR Convergence 2025) - "To guide precision repurposing, we applied a transcriptome-driven strategy to identify compounds that either mimic the molecular effects of standard therapies or reverse gene expression profiles associated with treatment resistance. Paired whole-blood transcriptomes from 31 SLE patients treated with rituximab (n=8), belimumab (n=13), or cyclophosphamide (n=10) were analyzed to define drug-specific signatures (absolute log₂FC > 0.58, p < 0.05)...Rituximab's signature aligned with mTOR blockers (everolimus, dactolisib), PI3K inhibitors (PIK-75, ZSTK474), JAK2 inhibitors (fedratinib) and agents downregulating the p38-MAPK pathway (OXA)... Our analysis delineates molecular correlates of therapeutic response and identifies candidate drugs capable of emulating molecular effects of standard SLE therapies or reversing gene expression patterns associated with treatment failure, offering a framework for drug repurposing in difficult-to-treat SLE."

IO biomarker • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • BCL2 • CDC37

High-throughput combination screening of Pidnarulex and other G-quadruplex ligands in multi-cell type tumor spheroids (AACR-NCI-EORTC 2025) - "To investigate the therapeutic potential of three G4 ligands—pidnarulex, APTO-253, and BRACO-19—a high-throughput drug combination screen was conducted in thirty-one multicellular tumor spheroids derived from patient tumors and established cancer cell lines. Brightfield imaging corroborated enhanced spheroid growth suppression in synergistic combinations. These findings underscore the context-dependent activity of G4 ligands and support the use of integrated functional and imaging-based approaches to characterize therapeutic combinations in physiologically relevant 3D cancer models."

Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • PIM1

High-throughput combination screening of Pidnarulex and other G-quadruplex ligands in multi-cell type tumor spheroids. (PubMed, SLAS Discov) - "To investigate the therapeutic potential of three G4 ligands-pidnarulex, APTO-253, and BRACO-19-a high-throughput drug combination screen was conducted in thirty-one multi-cell type tumor spheroids derived from patient tumors and established cancer cell lines. Brightfield imaging corroborated enhanced spheroid growth suppression from synergistic combinations. These findings underscore the context-dependent activity of G4 ligands and support the use of integrated functional and imaging-based approaches to characterize potential therapeutic combinations in physiologically relevant 3D cancer models."

Journal • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • PIM1

Senhwa Biosciences' CX-5461 Teams Up with Global PD-1 Leaders to Enter the Immunotherapy Arena, Targeting Multi-Billion Dollar Global Market (PRNewswire) - "The Company's novel investigational drug Pidnarulex (CX-5461) will be evaluated in combination with the approved PD-1 inhibitor Cemiplimab (Libtayo®), provided by Sanofi and Regeneron Pharmaceuticals, in a Phase 1/2 clinical trial for patients with microsatellite-stable colorectal cancer (MSS CRC) who are refractory to immune checkpoint inhibitors."

New P1/2 trial • Colorectal Cancer

A CONSERVED G-QUADRUPLEX IN HEPATITIS E VIRUS NEGATIVE-STRANDED RNA PROMOTES VIRAL REPLICATION VIA RNA STABILIZATION (AASLD 2025) - "To validate the existence of G4s in HEV, three G4 ligands (PDS, CX-5461, TMPyP4) were used to diverse HEV infection models (HepG2/C3A, Caco-2, Primary Gerbil Hepatocytes) for antiviral efficacy assessment... Collectively, these results demonstrate four conserved PQSs in HEV RNA capable of folding into stable parallel G4 structures in vitro. Notably, the NPQS-2 located on the HEV negative-stranded RNA is crucial for HEV, facilitating viral replication through RNA stabilization."

Hepatology • Infectious Disease • Inflammation

Testing the Effectiveness of the Anti-cancer Drug Pidnarulex (CX-5461) in Combination With Another Anti-cancer Drug Cemiplimab (REGN2810), in Treating Refractory Microsatellite Stable Colorectal Cancer (clinicaltrials.gov) - P1/2 | N=86 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Sep 2025 ➔ Dec 2025

Trial initiation date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor

Nucleolar stress facilitates islet β cell senescence via hijacking the DNA damage response pathways. (PubMed, iScience) - "Exposure to nucleolar stress inducers CX-5461 and actinomycin D (ActD) resulted in senescence-associated β-gal staining (SA-β-gal) activity in cultured β cells. Pharmacological inhibition of ATM with KU60019 strongly attenuated nucleolar stress-induced β cell senescence. Collectively, these findings identify nucleolar stress as a key upstream event in β cell senescence and highlight the γ-H2AX-ATM axis as a critical mediator of this process."

Journal • Ataxia • Diabetes • Immunology • Metabolic Disorders • Movement Disorders • Primary Immunodeficiency • CDKN1A • NPM1

Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer. (PubMed, Cell Death Discov) - "In this study, we examine the response of HGSOC cells to standard of care cisplatin chemotherapy and to the RNA Polymerase I transcription inhibitor CX-5461/Pidnarulex, two drugs that elicit a potent DNA damage response and growth arrest. Mechanistically, we demonstrate that senescent HGSOC cells have altered expression of regulators of iron metabolism leading to intracellular iron overload that underpins this targetable vulnerability. Together, we highlight elevated levels of iron as a TIS biomarker in HGSOC and the potential of inducing ferroptosis to eradicate residual HGSOC cells following initial therapy."

Journal • Hematological Disorders • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BCL2L1

ATRX cooperates with TOP2B for replication fork stability and DNA damage response through G-quadruplex regulation. (PubMed, Nucleic Acids Res) - "While etoposide similarly induces G4-related DNA damage, it does not affect the ATRX-TOP2B interaction, highlighting CX-5461's unique mechanism. Our findings establish TOP2B as a critical player in G4 resolution, reveal CX-5461's dual function as a TOP2B poison and G4 stabilizer, and propose G4-associated replication stress as a potential therapeutic target in ATRX-deficient gliomas."

Journal • Brain Cancer • CNS Disorders • Genetic Disorders • Glioma • Mental Retardation • Oncology • Solid Tumor • ATRX • MRE11A

Testing the Safety of Anti-Cancer Drug, CX-5461 (Pidnarulex), in Treating Lymphoma With Specific Changes in the MYC Gene (clinicaltrials.gov) - P1/2 | N=50 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Sep 2025 ➔ Dec 2025

Trial initiation date • B Cell Lymphoma • Burkitt Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Investigating Ribosome-targeting Therapies for the Treatment of Relapsed/refractory Multiple Myeloma (IMS 2025) - "Our findings provide insights into molecular mechanisms underlying the disruption in protein homeostasis in MM, and strong evidence to promote the clinical development of therapies targeting the ribosome for RRMM."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • CD8 • CTLA4 • LAG3 • PD-1 • TIGIT

Testing the Safety of the Combination of Anti-Cancer Drugs CX-5461 (Pidnarulex) and Trastuzumab Deruxtecan (T-DXd) for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Solid Tumors and Breast Cancer (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1 trial • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Combined inhibition of WEE1 by AZD1775 synergistically enhances CX-5461 mediated DNA damage and induces cytotoxicity in glioblastoma. (PubMed, Tissue Cell) - "Consequently, these results suggest that CX-5461 inhibited GBM progression by stabilizing G4, causing replication stress and exacerbating DNA damage. Targeting G4 structures, especially when combined with checkpoint inhibitors, provides a hopeful therapeutic approach to improve the effectiveness of GBM therapy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Testing the Effectiveness of the Anti-cancer Drug Pidnarulex (CX-5461) in Combination With Another Anti-cancer Drug Cemiplimab (REGN2810), in Treating Refractory Microsatellite Stable Colorectal Cancer (clinicaltrials.gov) - P1/2 | N=86 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1/2 trial • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor

Nucleolar protein DCAF13 promotes non-small cell lung cancer cell proliferation via facilitating rDNA transcription and ribosome biogenesis. (PubMed, J Biol Chem) - "Reduction of rDNA transcription by CX-5461, an RNA polymerase I inhibitor, significantly inhibited NSCLC cell proliferation...DCAF13 knockout inhibited NSCLC cell proliferation, colony formation, and migration, indicating that DCAF13 is a poor prognosis indicator of NSCLC. In summary, we found that DCAF13 promotes NSCLC cell proliferation by coordinating with TAF1A to regulate rDNA transcription and maintain high ribosome biogenesis."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DDB1

CX-5461-04: Study of CX-5461 in Patients With Solid Tumours and BRCA1/2, PALB2 or Homologous Recombination Deficiency (HRD) Mutation (clinicaltrials.gov) - P1 | N=52 | Recruiting | Sponsor: Senhwa Biosciences, Inc. | Trial completion date: Jun 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Solid Tumor • BRCA1 • BRCA2