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

US NCI Sponsors Senhwa Biosciences' Second Program-IND Submitted for Clinical Trial Targeting MYC-Aberrant Lymphoma (PRNewswire) - "Senhwa Biosciences...announced that US National Cancer Institute (NCI) sponsors Senhwa's second program IND has been submitted to US FDA for clinical trial targeting MYC-aberrant lymphoma. Following the initiation of the first trial using CX-5461 as a monotherapy in advanced solid tumors, the IND-submission of the second trial marks a milestone in the development of CX-5461."

IND • Lymphoma

Ribosome biogenesis is a therapeutic vulnerability in pediatric neuroblastoma. (PubMed, Biochimie) - "Here, using the well-established IMR-32 cell line along with a previously established panel of patient-derived neuroblastoma cell lines with varying MYCN status, we show that RNA polymerase I inhibition following exposure to CX-5461 and BMH-21 suppressed cell proliferation at nanomolar concentrations and induced ribosomal stress, leading to the activation of apoptosis and the p21 pathway...In conclusion, 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 relevance of targeting ribosome biogenesis as a novel approach for neuroblastoma treatment."

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

POLR1A inhibits ferroptosis by regulating TFAM-mediated mitophagy and iron homeostasis. (PubMed, Redox Biol) - "Notably, CX-5461, a first-in-class RNA PolI inhibitor currently in clinical trials, synergizes with GPX4 blockade to induce ferroptotic cell death both in vitro and in vivo. This therapeutic synergy extends beyond PM, suggesting broader relevance in ferroptosis-resistant cancers. Together, our findings reveal a novel mechanism of ferroptosis evasion and establish a promising combinatorial strategy to overcome therapy resistance in cancer."

Journal • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • ATF4 • GPX4 • TFAM

CX-5461 inhibits cell proliferation and induces ferroptosis of colorectal cancer cells by inactivating Nrf2 pathway. (PubMed, Cell Signal) - "The decreased Nrf2 subsequently down-regulates SLC7A11 and GPX4. In conclusion, these results demonstrated that CX-5461 induced ferroptosis through inhibiting SLC7A11/GPX4 axis by promoting ubiquitinization of Nrf2 in CRC cells, suggesting that CX-5461 may be a valuable candidate for anti-cancer agent in CRC."

Journal • Colorectal Cancer • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • BRCA1 • BRCA2 • GPX4 • SLC7A11

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)

New P1/2 trial • B Cell Lymphoma • Burkitt Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Targeting ribosomes reprograms the tumour microenvironment and augments cancer immunotherapy. (PubMed, Br J Cancer) - "These findings unravel previously unrecognized roles of cellular ribosome biogenesis in sustaining immunosuppressive non-cancer cells. Our work unveils that ribosome biogenesis blockade could reinstate immunosurveillance and provide novel strategies to enhance the ICB efficacy in patients with poor immunogenicity."

IO biomarker • Journal • Oncology

Prospective Isolation According to Melanin Pigment Content of Melanoma Cells With Heterogeneous Potentials for Disease Propagation. (PubMed, Pigment Cell Melanoma Res) - "In proof-of-concept studies, the latter was targeted by topoisomerase 2 beta targeting with CX-5461, which induced senescent HPC phenotypes and irreversible loss of clonogenic activity. These data indicate an 'inverted pyramid' hierarchical model of melanoma cell propagation wherein abundant LPCs frequently renew their own malignant potential to propagate disease but also infrequently generate HPCs that spontaneously lose this ability in a manner that might be exploited as an anti-melanoma strategy."

Heterogeneity • Journal • Melanoma • Oncology • Solid Tumor • MYC

Optimizing GBM organoid construction with hydrogel-based models: GelMA-HAMA scaffold supports GBM organoids with clonal growth for drug screening. (PubMed, Cell Transplant) - "GelMA-HAMA(GH) could replace Matrigel preserving the characteristics and proliferative capacity of GSCs and supported the formation of more compact spherical clones than MH did. Further experimentation with ribosomal inhibitor CX5461 and CX5461 + IFNβ indicated that GH-based GBM organoid model constituted an efficient system for GBM drug testing, discovery, and precision medicine."

Journal • Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • IFNB1

Lysosomal membrane permeabilization enhances the anticancer effects of POLR1 (RNA polymerase I) transcription inhibitors. (PubMed, Autophagy) - "This study investigates this aspect in the context of two potent POLR1 (RNA polymerase I) transcription inhibitors, CX-3543 (quarfloxin) and CX-5461 (pidnarulex). Additionally, combining CX-3543 with the chloroquine derivative DC661 more effectively reduced the fibrosarcoma growth in immunocompetent mice than either agent alone. Altogether, our results reveal an unanticipated lysosome-related mechanism that contributes to cancer cell resistance to POLR1 inhibitors and propose a strategy to overcome this resistance.Abbreviations: ATG7: autophagy related 7; ATG13: autophagy related 13; Baf A1: bafilomycin A1; CTSB: cathepsin B; DKO: double knockout; G4: Guanine quadruplex; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LGALS3: galectin 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; NCL: nucleolin; POLR1: RNA polymerase I;..."

Journal • Fibrosarcoma • Oncology • Sarcoma • Solid Tumor • ATG7 • CTSB • LAMP1 • LAMP2 • LGALS3 • MAP1LC3B • NCL • SQSTM1 • TFE3 • TFEB

Single-Molecule Detection on Intrastrand Interactions among G4 Clusters. (PubMed, Anal Chem) - "Compared to CX-5461, PDS is a more effective inhibitor of c-KIT. This single-molecule detection method provides robust support for investigating the intrastrand interactions between consecutive G4 structures."

Journal • Oncology

Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence. (PubMed, Cancer Immunol Immunother) - "Interestingly, alisertib, etoposide and CX5461 rendered senescent HCC vulnerable to be targeted by either T-cell-engaging bispecific antibodies or CAR NK cells. Collectively, our study indicates that heterogenous, but selective features of HCC senescence may be exploited by different immunotherapeutic approaches."

Heterogeneity • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CD276 • CD40 • FAS • HER-2

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

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

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