zotiraciclib (TG02) / S*BIO, Cothera Biosci, Adastra Pharma - LARVOL DELTA

Inhibition of CDKs Enhances Efficacy of Anti-EGFR Therapy in Chordoma. (PubMed, Mol Cancer Ther) - "Importantly, co-treatments exhibited greater inhibition of tumor growth than single treatments in cell line- and patient-derived xenograft models. Taken together, our data revealed that THZ1 or TG02 enhanced in vitro and in vivo efficacy of afatinib, suggesting a potential novel combination therapeutic strategy for patients with chordoma."

Journal • Chordoma • Oncology • MCL1

Phase I/II study of zotiraciclib for recurrent malignant gliomas with IDH mutations: results of the phase I study (SNO 2025) - "ZTR at the RP2D of 200mg, q3D, 3wks on/1wk off in a 28-day cycle is well tolerated. Objective responses suggest activity of this regimen in IDH-mutant gliomas, supporting continued investigation."

P1/2 data • Brain Cancer • Glioma • High Grade Glioma • Solid Tumor

Phase I/II study of zotiraciclib for recurrent malignant gliomas with IDH mutations: results of the phase I study (SNO 2025) - "ZTR at the RP2D of 200mg, q3D, 3wks on/1wk off in a 28-day cycle is well tolerated. Objective responses suggest activity of this regimen in IDH-mutant gliomas, supporting continued investigation."

P1/2 data • Brain Cancer • Glioma • High Grade Glioma • Solid Tumor

Phase I/II study of zotiraciclib for recurrent malignant gliomas with IDH mutations: results of the phase I study (WFNOS 2025) - "ZTR at the RP2D of 200mg, q3D, 3wks on/1wk off in a 28-day cycle is well tolerated. Objective responses suggest activity of this regimen in IDH-mutant gliomas, supporting continued investigation."

P1/2 data • Brain Cancer • Glioma • High Grade Glioma • Solid Tumor

Phase I/II study of zotiraciclib for recurrent malignant gliomas with IDH mutations: results of the phase I study (WFNOS 2025) - "ZTR at the RP2D of 200mg, q3D, 3wks on/1wk off in a 28-day cycle is well tolerated. Objective responses suggest activity of this regimen in IDH-mutant gliomas, supporting continued investigation."

P1/2 data • Brain Cancer • Solid Tumor

INTEGRATING PATIENT-DERIVED MODELS AND MULTI-OMIC PROFILING: A PRECISION MEDICINE PLATFORM FOR NEUROBLASTOMA DRUG DISCOVERY (SIOP 2025) - "Conclusions We establish NB patient-derived cell, organoid, xenograft and multi-omics-based platform for personalized therapy of NB. In a brain metastasis NB, CGP60474, SB1317 and TAK-960 were identified to have anti-NB effect and validated in a NB cell line."

Clinical • Neuroblastoma • Solid Tumor • CHGA • HOXB6 • PHOX2B

Transcriptional condensates enrich phosphorylated PRMT2 to stimulate H3R8me2a deposition and hypoxic response in glioblastoma. (PubMed, Sci China Life Sci) - "Moreover, the combination of TG02 and temozolomide, the standard chemotherapy for GBM, significantly inhibits tumor progression in mouse xenograft models, an effect partially mediated by targeting PRMT2S12 phosphorylation. Our study uncovers the role of transcriptional condensation in enhancing PRMT activity, reveals a new mechanism for CDK9 inhibitors in modulating context-dependent transcriptional programs, and proposed a combinatorial therapeutic strategy against GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • PRMT2

A Phase I/II Study of Zotiraciclib for Recurrent Malignant Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations (clinicaltrials.gov) - P1/2 | N=96 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2029 ➔ Aug 2032 | Trial primary completion date: Aug 2025 ➔ Aug 2028

Trial completion date • Trial primary completion date • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • IDH1 • IDH2

Endogenous HiBiT-tagging of PAX3::FOXO1 reveals that CDK inhibitors downregulate the fusion oncogene, and demonstrate synergy effects when combined with vincristine and irinotecan [WITHDRAWN] (AACR 2025) - "BACKGROUND: Oncogenic fusion genes are attractive therapeutic targets due to their tumor-specific expression and driver roles in cancer. By HiBiT tagging the fusion oncogene P3F, we identified 182 drugs that suppress P3F levels. One of the top hits, TG02, showed in vivo efficacy, indicating that FP-RMS is susceptible to multi-CDK inhibition. Decreased occupancy of Pol2S2 in the gene body of P3F targets indicates that the mechanism of TG02 is primarily through transcriptional inhibition of P3F and its targets."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • BRD4 • CDK7 • CDK9 • PAX3

Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib. (PubMed, iScience) - P1/2 | "We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas (NCT05588141)."

Journal • Brain Cancer • CNS Tumor • Glioma • Metabolic Disorders • Oncology • Solid Tumor • CDK9

A non-randomised open-label exploratory 'window of opportunity' study of TG02 treatment in patients with locally advanced primary and recurrent RAS mutant colorectal cancer. (PubMed, Heliyon) - P1 | "Low numbers limit conclusive clinical outcome reporting. High PD-1 expression on post-treatment TILs encourages the addition of an immune checkpoint inhibitor to TG02 and potentially other studies of peptide vaccines in future studies."

IO biomarker • Journal • Colorectal Cancer • Immunology • Oncology • Solid Tumor • CSF2 • KRAS • RAS

Repurposing SSRI/SNRI targeting neurotransmitter signaling to overcome resistance to CDK9 inhibitors in diffuse midline glioma (SNO 2024) - "Cyclin-dependent kinase 9 (CDK9i) inhibitors such as zotiraciclib (ZTR) are in clinical trials for glioma, but CDK9i treatment alone may be ineffective due to the development of resistance...Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres by BLISS analysis and show that co-treatment with CDK9i and SSRI/SNRI strongly induces the apoptotic marker cleaved caspase 3 and reduces the CDK9 target phos-Pol2Ser2...Finally, preclinical studies show that co-treatment with low doses of AZD4573 and sertraline reduces the growth of orthotopic DMG xenografts and prolongs overall survival. Taken together, these data suggest that SSRI/SNRI and CDK9i might be used in combination to synergistically reduce DMG growth and overcome CDK9i resistance."

Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • CASP3 • CDK9

Phase I clinical study of a multi-kinase inhibitor TG02 capsule for the treatment of recurrent high-grade gliomas with failed temozolomide treatment in Chinese patients. (PubMed, Chemotherapy) - "TG02 capsule 150mg twice a week is safe and tolerable in Chinese patients with recurrent high-grade gliomas. Patients who failed to temozolomide showed obvious tumor reduction when switching to TG02 capsule. The efficacy for recurrent gliomas warrant further investigation."

Journal • P1 data • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Malignant Glioma • Oncology • Solid Tumor

Impact of Zotiraciclib on Glioma Tumor Microenvironment (SNO 2024) - "The immunophenotyping performed for this study demonstrates that zotiraciclib does not alter the mouse glioma immune microenvironment. Complementary studies using human immune cells shows that zotiraciclib does not suppress the activation of cytotoxic T cells but reduces the polarization of immunosuppressive M2 macrophages, supporting combining zotiraciclib and immune stimulatory approach in glioma treatment."

Biomarker • Tumor microenvironment • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CD14 • CD163 • CD8 • IDH1 • IFNG • IL2RA • MRC1 • TNFA

Identification of Hub of the Hub-Genes From Different Individual Studies for Early Diagnosis, Prognosis, and Therapies of Breast Cancer. (PubMed, Bioinform Biol Insights) - "Finally, we suggested hHubGs-guided top-ranked 10 candidate drug molecules (SORAFENIB, AMG-900, CHEMBL1765740, ENTRECTINIB, MK-6592, YM201636, masitinib, GSK2126458, TG-02, and PAZOPANIB) by molecular docking analysis for the treatment against BC. The literature review also supported our findings much more for BC compared with the results of individual studies. Therefore, the findings of this study may be useful resources for early diagnosis, prognosis, and therapies of BC."

Journal • Breast Cancer • Oncology • Solid Tumor • CCNA2 • CCNB1 • CCND1 • CDK1 • EGFR • ER • TOP2A • TP53

Zotiraciclib for newly diagnosed or recurrent glioblastoma: updated outcome and biomarker analysis (EAN 2024) - "In groups A and B, the maximum tolerated dose (MTD) of Zotiraciclib in elderly patients, in combination with radiotherapy alone (group A) or temozolomide alone (group B), by O6- methylguanine DNA methyltransferase promoter methylation status, were determined. Zotiraciclib exhibits overlapping toxicity with alkylators and low single agent clinical activity. The role of c- MYC and MCL- 1 as therapeutic targets and the diagnostic value of extracellular vesicles in peripheral blood in glioblastoma warrant further study."

Biomarker • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Gastroenterology • Gastrointestinal Disorder • Glioblastoma • Hematological Disorders • Hepatology • Neutropenia • Oncology • Solid Tumor • MYC

Zotiraciclib for newly diagnosed or recurrent glioblastoma: Updated outcome and biomarker analysis. (ASCO 2024) - "In groups A and B, the maximum tolerated dose (MTD) of Zotiraciclib in elderly patients, in combination with radiotherapy alone (group A) or temozolomide alone (group B), stratified by O 6 -methylguanine DNA methyltransferase promoter methylation status, were determined. Zotiraciclib exhibits overlapping toxicity with alkylating agents which are the cornerstone of medical treatment for glioblastoma. Its single agent clinical activity in the recurrent setting was low. The role of c-MYC and MCL-1 as therapeutic targets and the diagnostic value of extracellular vesicles in peripheral blood in glioblastoma warrant further study."

Biomarker • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Gastroenterology • Gastrointestinal Disorder • Glioblastoma • Hematological Disorders • Hepatology • Neutropenia • Oncology • Solid Tumor • CDK9 • MYC

Focus on current and emerging treatment options for glioma: A comprehensive review. (PubMed, World J Clin Oncol) - "This review places a particular focus on immunotherapies, discussing promising agents such as Zotiraciclib and Lerapolturev...Exploration of immunotherapy extends to Pembrolizumab, Nivolumab, and Entrectinib, revealing the challenges and variabilities in patient responses. Despite promising preclinical data, the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment, emphasizing the critical need to understand resistance mechanisms...In addition to advancements in cancer vaccine development, this review highlights the evolving landscape of LGG treatment, emphasizing a shift toward personalized and targeted therapies. Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Pediatrics • Solid Tumor

Endogenous HiBiT-tagging of PAX3-FOXO1 reveals downregulation of the fusion oncogene by CDK inhibitors and has synergy with vincristine (AACR 2024) - "Background: Oncogenic fusion genes are attractive therapeutic targets due to their tumor-specific expression and driver roles in cancers. We validated HiBiT tagging of P3F by Western. Both P3F-HiBiT and unmodified P3F activated the same gene sets in fibroblasts by RNA-seq Gene Set Enrichment Analysis (GSEA). ChIP-seq using HiBiT antibody for P3F-HiBiT matched the genomic locations from ChIP-seq with P3F antibody in RH4 and SCMC."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • BRD4 • CDK1 • CDK4 • CDK9 • PAX3

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications. (PubMed, J Med Chem) - "Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials...Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors."

Journal • Review • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CDK9

[PREPRINT] Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib (bioRxiv) - "Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas."

Preclinical • Preprint • CNS Tumor • Glioma • Oncology • Solid Tumor

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial. (PubMed, Eur J Cancer) - P1 | "TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study."

Journal • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Disorders • CNS Tumor • Epilepsy • Gastroenterology • Gastrointestinal Disorder • Glioblastoma • Hematological Disorders • Hepatology • Neutropenia • Oncology • Solid Tumor • CDK9 • MCL1 • MYC

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: the EORTC 1608 STEAM trial (Eur J Cancer) - P1 | N=71 | STEAM (NCT03224104) | "The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival."

P1 data • Astrocytoma • Glioblastoma

The promising impact of Bemcentinib and Repotrectinib on sleep impairment in Alzheimer's disease. (PubMed, J Biomol Struct Dyn) - "Multiple compounds from three biomolecule libraries (719 compounds; ChemDiv:366 - ChEMBL:180 - PubChem:173) were evaluated for potential binding affinity and safety using AutoDock Vina and pkCSM, respectively, resulting in the selection of four candidate compounds (Lestaurtinib, Repotrectinib, Bemcentinib, and Zotiraciclib). We report Bemcentinib and Repotrectinib, formerly prescribed for cancer, as potential inhibitors of the CK1 δ. Besides their high binding affinity compared to ATP, they can inhibit all ATP-binding sites and alter the tau binding stability.Communicated by Ramaswamy H. Sarma."

Journal • Alzheimer's Disease • CNS Disorders • Insomnia • Oncology • Sleep Disorder

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: final results of the EORTC 1608 STEAM trial (SNO 2023) - P1 | "Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Larger randomized trials are required to explore activity in combination with RT or TMZ. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study."

Clinical • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Disorders • CNS Tumor • Epilepsy • Gastroenterology • Gastrointestinal Disorder • Glioblastoma • Hematological Disorders • Hepatology • Neutropenia • Oncology • Solid Tumor • CDK9 • MYC