COH29 / City of Hope, Novonco Therap - LARVOL DELTA

BAZ1A IN NEUROBLASTOMA: BIOLOGICAL FUNCTIONS, MOLECULAR MECHANISMS, AND IDENTIFICATION OF TARGETED SMALL MOLECULE INHIBITORS (SIOP 2025) - "Notably, 1,2,3,6-Tetragalloylglucose, Stafib-1, and COH29 achieved nearly 100% inhibition, while MST-312 exhibited an 80% inhibition rate, remaining stable across varying concentrations... BAZ1A significantly enhances the proliferation, colony formation, invasion, and migration abilities of NB cells. It may drive EMT and promote NB metastasis by activating the PI3K/AKT pathway and regulating the transcription factor ZEB2. The identified three small molecule inhibitors targeting BAZ1A effectively inhibit the proliferation of NB cells in vitro, representing potential novel therapeutic agents for NB."

Nephrology • Neuroblastoma • Solid Tumor • CDH1 • CDH2 • MYCN • ZEB2

RNR Inhibitor COH29 in Treating Patients With Solid Tumors That Are Refractory to Standard Therapy or For Which No Standard Therapy Exists (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Solid Tumor

Targeting RRM2: A Dual Approach to Apoptosis and Cell Cycle Control in Atypical Teratoid Rhabdoid Tumors (EACR 2025) - "Additionally, we evaluated the therapeutic efficacy of COH29, a pharmacological inhibitor of RRM2, in both in vitro ATRT cell models and in vivo orthotopic mouse model... Our findings establish RRM2 as a critical oncogenic factor in ATRT and highlight its potential as a therapeutic target. By disrupting both DNA damage response and cell cycle regulation, RRM2 inhibition presents a promising strategy for ATRT treatment. These insights provide a strong foundation for the development of novel therapeutic approaches aimed at improving outcomes for patients with this devastating pediatric tumor."

CNS Tumor • Cognitive Disorders • Embryonal Tumor • Oncology • Pediatrics • Rhabdoid Tumor • Sarcoma • E2F1 • RRM2

Mechanisms of AICAr-Induced Acute Myeloid Leukemia Differentiation: Role of Ribonucleotide Metabolism and Replication Stress (EACR 2025) - "We also found that cytarabine (AraC), a standard chemotherapy agent, promotes differentiation via replication stress and Chk1 activation, a mechanism shared with pyrimidine synthesis inhibitors...Inhibition studies were conducted using COH29 and hydroxyurea (HU) as inhibitors of ribonucleotide reductase (RNR), MK1775 as a Wee1 inhibitor, and siRNA targeting Wee1.Result and Metabolomic analysis revealed that pyrimidine and purine nucleotides were among the most differentially regulated metabolites, decreasing in brequinar- and AICAr-treated samples while increasing in AraC-treated samples... Our findings suggest that ribonucleotide metabolism regulates AML differentiation, with Wee1 and RNR activation occurring downstream of replication stress."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CHEK1 • RRM2

TCPTP inhibition as a novel therapeutic strategy for esophageal squamous cell carcinoma: discovery and efficacy of COH29. (PubMed, Biochem Pharmacol) - "Flow cytometry analysis revealed that COH29 treatment caused cell cycle arrest in the G1 phase in ESCC cells. In vivo studies further validated COH29's robust growth suppression of ESCC, highlighting its potential as a therapeutic agent."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • GCG • PTPN2

RNR Inhibitor COH29 in Treating Patients With Solid Tumors That Are Refractory to Standard Therapy or For Which No Standard Therapy Exists (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Dec 2024 ➔ Jun 2025

Trial completion date • Oncology • Solid Tumor

RRM2 inhibition alters cell cycle through ATM/Rb/E2F1 pathway in atypical teratoid rhabdoid tumor. (PubMed, Neoplasia) - "Our study highlights the role of ATM/Rb/E2F1 pathway in controlling cell cycle arrest and apoptosis in response to RRM2 inhibition-induced DNA damage. This provides insight into the therapeutic benefits of COH29 and suggests targeting this pathway as a potential treatment for ATRT."

Journal • Brain Cancer • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor • E2F1 • HRD • RRM2

COH29 treatment induces alterations in the cell cycle and suppresses the DNA damage response in ATRT through the ATM-Rb-E2F1 pathway (EACR 2024) - "Furthermore, this suppression blocks DNA damage repair mechanisms, potentially prompting cells to exit the cell cycle and undergo apoptosis.Conclusion Our findings highlight the critical role of the ATM-Rb-E2F1 signaling pathway in orchestrating DNA damage-induced cell cycle arrest and subsequent activation of apoptosis during COH29 treatment. This insight sheds light on the molecular mechanisms underlying the therapeutic effects of COH29 and highlights the potential of targeting this pathway for therapeutic intervention in ATRT."

CNS Tumor • Oncology • Rhabdoid Tumor • Sarcoma • E2F1 • HRD • RRM2

Identification of FTY720 and COH29 as novel topoisomerase I catalytic inhibitors by experimental and computational studies. (PubMed, Bioorg Chem) - "Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1."

Journal • Breast Cancer • Oncology • Solid Tumor • TOP1

RNR Inhibitor COH29 in Treating Patients With Solid Tumors That Are Refractory to Standard Therapy or For Which No Standard Therapy Exists (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Oncology • Solid Tumor

Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor. (PubMed, J Exp Clin Cancer Res) - "Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT."

Journal • Oncology • Rhabdoid Tumor • Sarcoma • RRM2

The key cellular senescence related molecule RRM2 regulates prostate cancer progression and resistance to docetaxel treatment. (PubMed, Cell Biosci) - "Our findings suggest that RRM2 regulates docetaxel resistance in prostate cancer by stabilizing ANXA1-mediated activation of the PI3K/AKT pathway. Targeting RRM2 or ANXA1 may offer a promising therapeutic strategy to overcome docetaxel resistance in prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA1 • RRM2

RRM2 inhibition by COH29 is a potential therapeutic strategy for atypical teratoid rhabdoid tumors (AACR 2023) - "Our study identified RRM2 as a potential mediator of oncogenic cellular functions in ATRT cell lines. We propose that highly expressed RRM2 is associated with poor patient outcomes, and inhibition of RRM2 by COH29 may present a significant therapeutic value in ATRT."

CNS Tumor • Oncology • Rhabdoid Tumor • Sarcoma • RRM2

RNR Inhibitor COH29 in Treating Patients With Solid Tumors That Are Refractory to Standard Therapy or For Which No Standard Therapy Exists (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: City of Hope Medical Center | Suspended ➔ Active, not recruiting | N=19 ➔ 12 | Trial completion date: Dec 2022 ➔ Dec 2023

Enrollment change • Enrollment closed • Trial completion date • Oncology • Solid Tumor • H2AX