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

TERT Reactivation in Thyroid Cancer: Mechanisms, Clinical Implications, and Therapeutic Opportunities. (PubMed, Eur Thyroid J) - "However, isolated TERT promoter mutations are more often associated with intermediate risk tumours and comparatively better outcomes, underscoring the importance of molecular context. The recent approval of the telomerase inhibitor Imetelstat and the preclinical success of the rRNA transcription inhibitor CX5461 in restoring differentiation and iodine uptake support telomerase- and ribosome-targeted strategies as emerging therapeutic avenues for TERT-driven thyroid cancers."

Journal • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • TERT

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies. (PubMed, Nat Commun) - P1 | "These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977."

Journal • P1 data • Oncology • Solid Tumor • BRCA2 • DRD • HRD • PALB2

The UVA-induced single-base mutational signature of CX-5461 in human cells. (PubMed, Nucleic Acids Res) - "We do not observe strong single-base mutagenic activity of CX-5461 alone, under light-protected conditions. Our data define a human SBS mutagenesis signature for CX-5461 potentiated UVA mutations and emphasize the need for appropriate controls and light-exposure precautions when studying SBS activity of known photosensitizer molecules."

Journal • Tumor mutational burden • Oncology • TMB

Senhwa Biosciences…announced that it has completed enrollment in its Phase 1b expansion trial evaluating pidnarulex (CX-5461) monotherapy in patients with advanced solid tumors harboring BRCA1/2, PALB2, or other homologous recombination deficiency (HRD)-associated alterations (PRNewswire) - "With enrollment complete, the study will proceed to data review and reconciliation, database lock, and comprehensive statistical analysis. The Clinical Study Report (CSR) is expected in the first quarter of 2027. The final analysis is expected to inform decisions on indication prioritization, biomarker-based patient selection, potential combination strategies, and the next stage of CX-5461's clinical development....The Phase 1b trial evaluates CX-5461 monotherapy in heavily pretreated patients with advanced DNA repair-deficient solid tumors. Enrolled tumor types include pancreatic, breast, and ovarian cancers."

Enrollment closed • P1 data • Platinum resistant • Platinum sensitive • Breast Cancer • Ovarian Cancer • Pancreatic Cancer

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

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 | Recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Dec 2026 ➔ Aug 2026

Trial initiation date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • FBXW7 • MSI • MYC

The G-quadruplex ligand CX-5461 inhibits laryngeal cancer via inducing immunogenic cell death and remodeling the tumor immune microenvironment. (PubMed, Int Immunopharmacol) - "G4 is a novel prognostic biomarker for laryngeal cancer. CX-5461 exerts anti-laryngocarcinoma effects by inducing ICD and reshaping the tumor immune microenvironment, providing a strong preclinical rationale for combining CX-5461 with immune checkpoint blockade in laryngeal cancer treatment."

IO biomarker • Journal • Head and Neck Cancer • Laryngeal Cancer • Oncology • Solid Tumor • CALR • CD8 • CD80 • CD86 • H2AX • HMGB1 • IL12A • IL6 • PTPRC • TNFA

G-quadruplex DNA reprograms the photochemistry of CX-5461 toward radical-driven anticancer activity. (PubMed, Nucleic Acids Res) - "In vivo, light-activated CX-5461 suppresses tumor growth and extends survival in immunocompetent syngeneic models, eliciting hallmarks consistent with immunogenic genome stress. Collectively, these findings reposition CX-5461 as a clinically relevant scaffold for G4-associated photogenomic cancer therapy, while supporting a model in which broader oxidative DNA damage may also contribute to the biological response."

Journal • Oncology

Senhwa's CX-5461 Opens a New Frontier in Photoimmunotherapy; Multinational Study Published in Nucleic Acids Research (PRNewswire) - "The study further showed that light-activated CX-5461 not only directly damaged cancer cells but also induced ICD. When cancer cells die through an immunogenic process, they release or expose danger-associated signals, including cell-surface calreticulin, extracellular ATP and high-mobility group box 1 (HMGB1)....In preclinical mouse studies, animals whose tumors regressed after treatment with CX-5461 and light exposure showed suppressed tumor growth when subsequently challenged with the same cancer cells. The observation suggests that treatment may establish tumor-specific immune memory and supports further investigation of an in situ cancer vaccine concept."

Preclinical • Oncology

RAD54L coordinates the nucleolar DNA damage response to maintain rDNA stability. (PubMed, EMBO J) - "Under baseline conditions and replication stress induced by the Pol I transcription inhibitor CX-5461, RAD54L limits the accumulation of ssDNA and coordinates nDDR signaling. We further show that rDNA-DSBs induce RNA polymerase II-dependent RNA-DNA hybrids (R-loops) at intergenic rDNA regions, which facilitate nucleolar reorganization and cap formation and repair factor recruitment. Together, these findings establish RAD54L as a key regulator that coordinates replication stress response and rDNA repair, maintaining rDNA stability and genome integrity."

Journal • RAD51 • RAD54L

GEM and Senhwa Biosciences have formally executed a Share Purchase Agreement for up to NT$500 million (PRNewswire) - "Purchases under the SPA may occur from time to time at the election of certain shareholders, subject to the terms and conditions of the SPA....Under the framework of the SPA, the equity commitment from GEM provides additional financial flexibility and is expected to support continued investment in Senhwa's clinical pipeline, potential in-licensing opportunities, and AI-enabled pipeline prioritization and expansion. The company's lead assets are CX-5461 (pidnarulex) and CX-4945 (silmitasertib), two investigational oncology therapies being studied across multiple cancer indications."

Commercial • Solid Tumor

Structural insights into the binding of CX-5461 and MTR-106 to G-quadruplex DNA. (PubMed, Nucleic Acids Res) - "Their rigid polyaromatic scaffolds stacked with the 3'-end G-tetrad of G4, while their flexible side chains extended into the groove of QDH to enable spatial recognition. These findings elucidated the molecular basis of G4 recognition by CX-5461 and MTR-106, and provided a structural framework for the rational development of next-generation G4-targeted therapeutics with improved selectivity and efficacy."

Journal • Oncology • Myt1l

Therapy-Induced DNA G-Quadruplex Remodeling Promotes Treatment Resistance in Pediatric Medulloblastoma (ISPNO 2026) - "Importantly, small-molecule G4 ligands (CX-5461 and TMPyP4) disrupt APE1-G4 interactions, impair DNA damage repair, and sensitize MB cells to radiation in a therapy-adapted MB model. Collectively, our studies uncovered a novel epigenetic mechanism of therapy resistance in MB and established G4 structures as actionable therapeutic targets. By disrupting a DNA repair scaffolding mechanism rather than core repair enzymes, this strategy offers a rational path to enhance therapeutic efficacy without increasing genotoxic burden."

Clinical • Brain Cancer • Medulloblastoma • Pediatrics • Solid Tumor

Phase Ib expansion and dose optimization study of CX-5461 in patients with solid tumours enriched for DNA-repair deficiencies. (ASCO 2026) - P1 | "CX-5461 was tolerable and showed evidence of durable disease control in heavily pretreated pts, enriched for HRD/DDR alterations and post exposure to PARPi. The 250 mg/m² dose is established as the RP2D based on clinical data and RDI. Correlative studies are ongoing."

Clinical • P1 data • Breast Cancer • Oncology • Ovarian Cancer • Pancreatic Adenocarcinoma • Renal Disease • Solid Tumor • Thrombocytopenia • BRCA • BRCA1 • BRCA2 • DRD • HRD

IVF culture conditions promote single nucleolus formation and elevate rRNA associated signals during mouse preimplantation development. (PubMed, Theriogenology) - "CX-5461 treatment reduced Y10b signal intensity and increased SN morphology significantly (P < 0.05), suggesting a relationship between rRNA level and nucleolar morphology. Taken together, these results suggest that the IVF culture environment, in which both fertilization and development occur entirely in vitro, is associated with changes in single nucleolus formation and rRNA associated signal during the preimplantation stage."

Journal • Preclinical • Gynecology

Exploiting ribosomal biogenesis dependence through RNA polymerase I inhibition in medulloblastoma. (ASCO 2026) - "These studies demonstrate that RNA polymerase I inhibition using CX-5461 has potent antitumor activity in high-risk medulloblastoma models, including survival benefit in an intracranial setting. These findings identify ribosome biogenesis as a therapeutic vulnerability in medulloblastoma and support continued translational development of CX-5461 toward future clinical evaluation in children with high-risk medulloblastoma."

Brain Cancer • Medulloblastoma • Solid Tumor

CX-5461 exerts pangenotypic anti-hepatitis E virus effect in preclinical models (EASL 2026) - "Specific antiviral drugs targeting HEV are still lacking, and the use of ribavirin is limited by adverse effects or treatment failure. These findings demonstrate that the HEV genome contains G4s, and the CX-5461 exhibits robust antiviral activity both in vitro and in vivo. CX-5461 showed promising pangenotypic efficacy in multiple preclinical models. These results support CX-5461 as a novel strategy for treating acute and chronic HEV infection."

Preclinical • Fibrosis • Hepatology • Infectious Disease • Inflammation • Liver Cirrhosis

Endothelial RNA polymerase I, which is regulated by SPEN, is a target for improving anti-PD-1 immunotherapy of cancer. (PubMed, Biochem Pharmacol) - "A combined therapy of anti-PD-1 with CX-5461, a small-molecule inhibitor of RNAPI yielded better tumor inhibition than monotherapy with anti-PD-1 alone. This was attributable to increased T-cell infiltration and a marked expansion of polyfunctional CD8⁺ T-cells capable of producing both IFN-γ and TNF-α. In summary, our study identifies endothelial RNAPI, which is regulated by SPEN, as a target of normalizing tumor-immune microenvironment and that the RNAPI inhibitor, which is under clinical trial, is potentially useful to improve PD-1 blocker in cancer therapy."

IO biomarker • Journal • Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • IFNG • SPEN • TNFA

Senhwa Biosciences Launches Global Study, Targeting Breakthrough in Hard-to-Treat Cancers with CX-5461 and Tislelizumab Combination (PRNewswire-Asia) - "The Company has also submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA)....The study will evaluate Senhwa's first-in-class investigational drug, Pidnarulex (CX-5461), in combination with BeOne Medicines' marketed PD-1 inhibitor, tislelizumab, across multiple advanced or metastatic solid tumors, including pancreatic cancer, colorectal cancer, and melanoma-areas with significant unmet medical needs. The global multi-center design is expected to accelerate clinical validation while enhancing the asset's visibility, supporting future out-licensing and commercialization opportunities."

IND • New trial • Colorectal Cancer • Melanoma • Pancreatic Cancer

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: Dec 2026 ➔ Mar 2027 | Trial primary completion date: Dec 2025 ➔ Mar 2027

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • BARD1 • BRCA1 • BRCA2 • BRIP1 • CCNE1 • CDC25A • CDC25C • CDK12 • CHEK1 • CHEK2 • CREBBP • DYNLL1 • ERCC4 • FANCA • FANCB • FANCC • FANCD2 • FANCE • FANCF • FANCG • FANCI • FANCL • FANCM • GNRP • KMT2C • KMT2D • MAD2L2 • MUS81 • NBN • RAD17 • RAD50 • RAD51 • RAD51B • RAD51C • RAD51D • RAD54L • RBBP8 • RFWD3 • SLFN11 • SLX4 • XRCC2

In vivo CRISPR knockout screen reveals ribosome biogenesis as a driver and a potential therapeutic target for melanoma metastasis. (AACR 2026) - "Importantly, pharmacological inhibition with CX-5461 (Polr1 inhibitor) significantly slowed down the primary tumor growth and dramatically decreased the number of lung metastases...Indeed, western blot analysis of the cells with Polr1a KD confirmed that a decrease in Polr1a level is associated with the decrease of p52 and ReIB, which are the key proteins responsible for the activation of the non-canonical NF-κB pathway. Re-expression of RelB in the cells with Polr1a KD rescued the migration phenotype, demonstrating that Polr1a regulates melanoma migration ability in an NF-κB-dependent manner.Overall, these results suggest Polr1a as a prospective new target for the treatment of metastatic melanoma and shed light on a potential mechanism responsible for the pro-metastatic effect of this gene."

Preclinical • Melanoma • Oncology • Solid Tumor • RELB

(E,E)-bisantrene silences c-MYC expression by stabilizing its promotor region G-quadruplex (AACR 2026) - "(E,E)-bisantrene binds to and stabilizes the G4 structure contained within the c-MYC promotor region, leading to silencing of c-MYC gene expression. These studies support clinical evaluation of (E,E)-bisantrene as a new G4-targeting drug in MYC-driven tumors."

Oncology • ATF4 • MYC

Pilot study of pidnarulex pharmacodynamics in patients with advanced solid tumors (AACR 2026) - P1 | "Study success requires 16 evaluable biopsies per cohort, with ≥3 patients (19%) showing a Rad51 response, providing 90% power to detect a true 30% Rad51-positive response rate at a 5% false-positive rate.Funded by NCI Contract No. HHSN261201500003I."

Clinical • Metastases • PK/PD data • Oncology • Solid Tumor • ARID1A • BAP1 • BARD1 • BRCA1 • BRCA2 • BRIP1 • CDK12 • CHEK1 • CHEK2 • IDH1 • IDH2 • MRE11A • NBN • PALB2 • RAD50 • RAD51 • RAD51B • RAD54L • RPA2 • TP53BP1

Photodynamic activation of CX-5461 enhances its anti-tumor efficacy (AACR 2026) - "CX-5461 is a photosensitizer that produces both type I and type II ROS, which increases its cytotoxic effects in vitro when exposed to UV light. The efficacy of CX-5461 in combination with UV treatment has been demonstrated in syngeneic models like CT26 and B16F10. These findings suggest that the phototoxic properties of CX-5461 could represent a novel therapeutic strategy for treating of cancers that are amenable to UV light exposure."

Clinical • Oncology • Ovarian Cancer • Solid Tumor

Enhancing CX-5461 therapy in TNBC through liposomal delivery and ATR inhibitor combination (AACR 2026) - "CX-5461 is a promising agent for DNA repair-deficient TNBC, with strong single-agent activity demonstrated in vitro and in vivo. Preliminary combination studies with Berzosertib revealed synergistic potential. Future in vivo studies will evaluate whether liposomal delivery and combination therapy can improve survival in TNBC."

Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • HRD