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

The G-quadruplex ligand CX-5461: an innovative candidate for disease treatment. (PubMed, J Transl Med) - "Lastly, this review highlights the targeted therapy strategy of CX-5461 based on nanomedicine delivery, particularly the drug delivery utilizing the nucleic acid aptamer AS1411, which contains a G4 motif to specifically target the highly expressed nucleolin on the surface of tumor cell membranes; It also anticipates the strategy of coupling CX-5461 with peptide nucleic acids and locked nucleic acids to achieve dual targeting, thereby realizing individualized G4-targeting by CX-5461. This review aims to provide a general overview of the progress of CX-5461 in recent years and suggest potential strategies for disease treatment involving ribosomal RNA synthesis, G4, and topoisomerase."

Journal • Review • Immunology • Infectious Disease • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • DRD • NCL • PALB2

Investigating the role of topoisomerase IIB in the regulation of antigen presentation pathway in high-grade serous ovarian cancer (AACR 2025) - "Recently, a small molecule inhibitor, CX-5461, was discovered to specifically target TOP2B. It has also completed Phase I clinical trials for solid tumor and hematological malignancies demonstrating its safety and efficacy in human patients. Understanding the role of TOP2B in cancer progression may lead to the development of a novel therapeutic strategy to improve overall survival of HGSOC patients."

IO biomarker • Epithelial Ovarian Cancer • Gynecologic Cancers • Hematological Malignancies • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CD8

TFEB-dependent signals confer resistance against chemotherapeutic drug-induced nucleolar stress (AACR 2025) - "4) Like gemcitabine, CX5461 impairs cell growth. Therefore, our results support the involvement of TFEB in chemoresistance. These TFEB-protective signals may be particularly relevant to cancers with high TFEB expression levels, such as pancreatic cancer."

Oncology • Pancreatic Cancer • Solid Tumor • CTSB • LAMP1 • NCL • TFEB

ADAR1 enhances ribosome biogenesis and triggers oncogenic translation (AACR 2025) - "Our study establishes a critical link between post-transcriptional RNA editing, tumor ribosome biogenesis, and oncogenic translation, addressing a key gap in the field. ADAR1 emerges as a pivotal regulator of onco-RiBi, and targeting ADAR1 in tumors with high expression using CX-5461 represents a promising therapeutic strategy."

IO biomarker • Oncology • Triple Negative Breast Cancer • ADAR • FBL • MCM2

Ribosome biogenesis is a therapeutic vulnerability in paediatric neuroblastoma. (PubMed, bioRxiv) - "Our findings demonstrate that inhibition of RNA polymerase I using CX-5461 and BMH-21 suppressed cell proliferation at nanomolar concentrations and induced ribosomal stress, leading to activation of apoptosis and the p21 pathway...Our study reinforces the therapeutic potential of ribosome biogenesis inhibition in neuroblastoma and expands the list of potential targets to include rRNA maturation factors. These findings highlight the promise of targeting ribosome biogenesis as a novel approach for neuroblastoma treatment."

Journal • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • FBL • MYCN

Testing How the Body Responds to the Drug CX-5461 (Pidnarulex) in Patients With Metastatic Solid Cancers (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Trial completion date: Mar 2027 ➔ Dec 2026 | Initiation date: Dec 2024 ➔ Sep 2025 | Trial primary completion date: Mar 2027 ➔ Dec 2026

Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Oncology • Solid Tumor • RAD51

RBIS regulates ribosome biogenesis to affect progression in lung adenocarcinoma. (PubMed, J Transl Med) - "Collectively, these studies suggested the close involvement of RBIS in the progression of lung adenocarcinoma, providing new insights for targeted therapeutic interventions involving ribosomes."

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

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

G-quadruplex stabilizer CX-5461 effectively combines with radiotherapy to target ATRX-deficient malignant glioma. (PubMed, Neuro Oncol) - "In totality, our work substantively demonstrates efficacy and defines mechanisms of action for G4 stabilization as a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation."

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

Loss of SETD2 disrupts ribosomal RNA transcription and processing to confer therapeutic vulnerabilities (IKCS 2024) - "Lastly, we identify synthetic lethality between SETD2 deletion or inhibition and CX-5461 and Actinomycin D, compounds which block rRNA transcription. Alterations in ribosome biogenesis leads to epithelial-to-mesenchymal transition and metastasis in many tumor types, and our future goal will be to investigate the role of SETD2, ribosomes and rRNA transcription in transformation and metastasis in ccRCC.Figure: OOPS-proteomics identifies SETD2 as a regulator of ribosome biogenesis. RNA binding proteins are isolated from control or SETD2 -knockout cells identifies that metabolic proteins interact more with RNA (top right quadrant) while proteins regulating ribosome biogenesis (highlighted in orange)"

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • SETD2

ECT2-PLXNB2 Signaling Inhibits Ribosome Biogenesis Leading to Kidney Fibrosis (KIDNEY WEEK 2024) - "CX5461 was administrated to inhibit rDNA transcription... Collectively, our findings indicated that blocking RiBi initiated G2/M arrest and senescence of TECs as well as kidney fibrosis. ECT2 mediated PLXNB2 decline was a potential mechanism accounting for the impaired RiBi in fibrosis."

Fibrosis • Immunology • ECT2 • RPL11 • RPL5 • TGFB1

US FDA issues Study May Proceed letter for the Pilot Study of Pidnarulex Pharmacodynamics in Patients with Advanced Solid Tumors, Sponsored by the US National Cancer Institute (PRNewswire) - "Senhwa Biosciences, Inc...today announced that FDA issues Study May Proceed letter for its developing drug Pidnarulex (CX-5461) in trial entitled 'Pilot Study of Pidnarulex Pharmacodynamics in Patients with Advanced Solid Tumors' sponsored by the US National Cancer Institute (NCI)....The study will assess whether Pidnarulex (CX-5461) induces a Rad51 response, in patients with and without homologous repair deficiency (HRD) genetic mutations....In addition to this monotherapy trial, the NCI is considering future clinical trials involving Pidnarulex (CX-5461) in combination with other therapies, such as immunotherapies and antibody-drug conjugates (ADCs)."

IND • Oncology • Solid Tumor

Oral administration of Sophora Flavescens-derived exosomes-like nanovesicles carrying CX5461 ameliorates DSS-induced colitis in mice. (PubMed, J Nanobiotechnology) - "Furthermore, SFELNVs promoted M2 polarization by miR4371c using miRNA sequencing. Our results suggest that SFELNVs@CX5461 represents a novel orally therapeutic drug that can ameliorate colitis, and a promising targeting strategy for safe UC therapy."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL1B • IL6 • TNFA

The Unique Pt(II)-Induced Nucleolar Stress Response and its Deviation from DNA Damage Response Pathways. (PubMed, J Biol Chem) - "The mechanisms of action for the platinum compounds cisplatin and oxaliplatin have yet to be fully elucidated, despite the worldwide use of these drugs. Finally, we compare Pt(II)-induced nucleolar stress with other small-molecule nucleolar stress-inducing compounds Actinomycin D, BMH-21, and CX-5461, and find that only Pt(II) compounds cause irreversible nucleolar stress. Taken together, these findings contribute to a better understanding of Pt(II)-induced nucleolar stress, its deviation from ATM/ATR-dependent DDR, and the possible influence of cell cycle on the ability of Pt(II) compounds to cause nucleolar stress."

Journal

Testing How the Body Responds to the Drug CX-5461 (Pidnarulex) in Patients With Metastatic Solid Cancers (clinicaltrials.gov) - P1 | N=40 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1 trial • Oncology • Solid Tumor • HRD • RAD51

Molecular basis of CX-5461-induced DNA damage response in primary vascular smooth muscle cells. (PubMed, Heliyon) - "In summary, we suggest that DNA replication stress may be the primary molecular event leading to downstream ATM/ATR and p53 activations in CX-5461-treated vascular smooth muscle cells. Our results provide further insights into the molecular basis of the beneficial effects of CX-5461 in proliferative vascular diseases."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • RAD51

Phase Ib expansion study of CX-5461 in patients with solid tumours and BRCA2 and/or PALB2 mutation (ESMO 2024) - P1 | "Pts were heavily pretreated with median number of 6 lines (2-10): 77% prior platinum, 41% bevacizumab and 86% PARPi. This Phase 1b study shows acceptable clinical tolerability and early signals of activity for CX-5461, including post PARP inhibition. Photosensitivity was manageable by preventive measures. Genomic data on resistance mechanisms is being analyzed."

Clinical • P1 data • Breast Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • BRCA1 • BRCA2 • PALB2

Senhwa Biosciences Announces IND Submission to US FDA for Pilot Study of Pidnarulex Pharmacodynamics in Patients with Advanced Solid Tumors sponsored by NCI (PRNewswire) - "Senhwa Biosciences, Inc...today announced that an Investigational New Drug (IND) application for Pidnarulex has been submitted to the U.S. FDA by the NCI. Senhwa' investigational drug, Pidnarulex (CX-5461), has been selected as an experimental drug in the NExT (NCI Experimental Therapeutics) cancer program, sponsored by the Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH), for a five-year period. This drug will be used in a pharmacodynamic (PD) pilot study involving patients with advanced solid tumors....In addition to this monotherapy trial, NCI is considering to plan future clinical trials for Pidnarulex (CX-5461) in combination with other therapies, including immunotherapy, antibody-drug conjugates (ADC), and PARP inhibitors."

IND • New trial • Solid Tumor

Senhwa Biosciences Presents Clinical Data Abstract on Pidnarulex at 2024 ESMO Congress (PRNewswire) - P1b | N=52 | NCT04890613 | Sponsor: Senhwa Biosciences, Inc. | "Among the 15 patients who were evaluable for drug response, 40% achieved clinical benefit, with stable disease (SD) being the best therapeutic response. Among these stable disease patients, there were 5 ovarian cancer patients, including 3 with BRCA1 somatic mutations, 1 with a BRCA1 germline mutation, and 1 with HRD-related gene mutations. All 5 patients had previously failed platinum chemotherapy and PARP inhibitor treatments, with 2 of them maintaining stable disease for at least 6 months following Pidnarulex treatment, offering renewed hope for advanced-stage ovarian cancer patients."

P1 data • Ovarian Cancer

Fibroblast growth receptor 1 is regulated by G-quadruplex in metastatic breast cancer. (PubMed, Commun Biol) - "Importantly, use of the clinical G-quadruplex-stabilizing compound, CX-5461, stabilized the FGFR1 G-quadruplex structures, blocked the transcriptional activity of the FGFR1 proximal promoter, decreased FGFR1 expression, and resulted in potent inhibition of pulmonary tumor formation. Overall, our findings suggest G-quadruplex-targeted compounds could be a potential therapeutic strategy to limit the cellular plasticity of FGFR1 overexpressing MBC."

Journal • Metastases • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • FGFR1

CX-5461 ameliorates disease in lupus-prone mice by triggering B-cell ferroptosis via p53-SLC7A11-ALOX12 pathway. (PubMed, Free Radic Biol Med) - "Molecular studies revealed that CX-5461 modulates CD36-Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4)-mediated glycerolipid metabolism in B cells, triggering ferroptosis through the p53- Solute Carrier Family 7 Member 11 (SLC7A11)- Arachidonate 12-Lipoxygenase (ALOX12) pathway, thereby decreasing IgG and Anti-Double-Stranded Deoxyribonucleic Acid (dsDNA) antibody levels and attenuating lupus. Collectively, these results suggest that CX-5461 holds promise as an effective candidate for targeted therapy against lupus."

Journal • Preclinical • Immunology • Inflammatory Arthritis • Lupus • Metabolic Disorders • Systemic Lupus Erythematosus • Transplantation • ACSL4 • CD36 • SCARB1 • SLC7A11

CX-5461 Preferentially Induces Top2α-Dependent DNA Breaks at Ribosomal DNA Loci. (PubMed, Biomedicines) - "Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs."

Journal • Hematological Malignancies • Lymphoma • Oncology • TOP2A

Unfolding rates of 1:1 and 2:1 complex of CX-5461 and c-MYC promoter G-quadruplexes revealed by single-molecule force spectroscopy. (PubMed, Biophys Rep) - "Furthermore, using the Bell-Arrhenius model to fit the unfolding force distributions, we determined the zero-force unfolding rates of 1:1, and 2:1 complexes to be (2.4 ± 0.9) × 10-8 s-1 and (1.4 ± 1.0) × 10-9 s-1 respectively. These findings provide valuable insights for the development of G4-targeted ligands to combat c-MYC-driven cancers."

Journal • Oncology • BRCA1 • BRCA2 • MYC

Senhwa Biosciences Clinical Data Abstract of Pidnarulex Accepted for Presentation at 2024 ESMO Congress (PRNewswire) - "Senhwa Biosciences' new drug Pidnarulex (CX-5461) has demonstrated efficacy in treating various solid tumors with BRCA2 or PALB2 gene defects. The abstract of this clinical trial has been selected for presentation at the 2024 European Society for Medical Oncology (ESMO) congress."

P1 data • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor

Alcohol exposure suppresses ribosome biogenesis and causes nucleolar stress in cranial neural crest cells. (PubMed, PLoS One) - "Similar results were obtained using a small molecule inhibitor of RNA Polymerase 1, CX5461, whereas p53-blocking morpholinos normalized craniofacial outcomes under high-dose alcohol...We conclude that alcohol causes the apoptosis of CNCs, at least in part, by suppressing ribosome biogenesis and invoking a nucleolar stress that initiates their p53-MDM2 mediated apoptosis. We further note that the facial deficits that typify PAE and some ribosomopathies share features including reduced philtrum, upper lip, and epicanthal distance, suggesting the facial deficits of PAE represent, in part, a ribosomopathy."

Journal • Alzheimer's Disease • Cognitive Disorders • MDM2 • RPL11