OTS964 / OncoTherapy - LARVOL DELTA

Novel treatment: CDK11 inhibition in rhabdoid tumor of the kidney (AACR 2026) - "OTS964 induced apoptosis via caspase-3 activation with G2/M cell cycle arrest, p53 upregulation, and RNA splicing disruption via SF3B1 inhibition. In future studies, we plan to investigate synergistic combination of CDK11 inhibition with existing therapies."

Kidney Cancer • Oncology • Renal Cell Carcinoma • Rhabdoid Tumor • Sarcoma • CASP3 • CDK1 • DNAJB1 • SF3B1 • SMARCB1

TARGETING ATYPICAL TERATOID/RHABDOID TUMOR: OTS964 SHOWS POTENT CYTOTOXICITY IN BT-12 AND JCRB CELLS (WRMC 2026) - "Current treatment regimens are not standardized and involve some combination of vincristine, carboplatin, etoposide, cyclophosphamide, cisplatin, dactinomycin, and doxorubicin. OTS964 demonstrated strong dose-dependent cytotoxicity against BT-12 and JCRB cells. The results highlight the need for future studies to determine the in vitroefficacy of OTS964 in combination with Navitoclax and Vorinostat, as well as the in vivoefficacy of OTS964 to assess its therapeutic potential in AT/RT cell lines."

Oncology • Rhabdoid Tumor • Sarcoma • CDK1

OTS964 EXHIBITS POTENT CYTOTOXICITY AGAINST THE HIGH-RISK NEUROBLASTOMA CELL LINES SK-N-DZ AND SK-N-BE (WRMC 2026) - "OTS964 demonstrates potent cytotoxicity in high-risk neuroblastoma cell lines, with enhanced efficacy when combined with navitoclax. These findings support further investigation using in vivomodels to evaluate the potential of OTS964 as a therapeutic agent for high-risk neuroblastoma. Figure 1.Combination treatment of OTS964 with Navitoclax and Vorinostat in SK-N-DZ neuroblastoma cell lines."

IO biomarker • Preclinical • Neuroblastoma • Solid Tumor • CDK1 • SF3B1

Targeting CDK11 in Rhabdoid Tumor of the Kidney. (PubMed, Cancers (Basel)) - "CDK11 inhibition by OTS964 effectively suppresses RTK growth through cell cycle arrest and RNA splicing inhibition, leading to apoptosis. OTS964 shows potent anti-tumor activity and tolerability, supporting CDK11 as a promising therapeutic target for RTK and related SMARCB1-deficient cancers."

Journal • Kidney Cancer • Oncology • Pediatrics • Renal Cell Carcinoma • Rhabdoid Tumor • Sarcoma • CASP3 • CDK1 • ITGAM • SF3B1 • SMARCB1

Small molecule splicing modulators that disrupt O-GlcNAc homeostasis. (PubMed, Nat Commun) - "Here we report the results of three parallel drug repurposing screens against the O-GlcNAc cycling enzymes in cells and in vitro that reveal kinase inhibitors GSK690693 and Y-33075 act as splicing modulators that disrupt O-GlcNAc homeostasis and simultaneously downregulate OGT and OGA. Evaluation of a panel of splicing modulators revealed three additional potent compounds (OTS964, indisulam, GNF2133) that similarly downregulate OGT and OGA with distinct splicing profiles. These findings reveal previously unobserved splicing modulator chemotypes and approaches to disrupt O-GlcNAc homeostasis."

Journal • OGA • OGT

An AKR1C3-activated kinase inhibitor prodrug. (PubMed, RSC Chem Biol) - "OBI-3424, a prodrug of a DNA alkylating agent, is a prominent example of this strategy. To extend this concept to selective enzymatic inhibitors, we have developed AKR1C3-activated prodrugs of OTS964, a CDK11 inhibitor...These results demonstrate that the AKR1C3-activated prodrug strategy can be used to convert selective kinase inhibitors into context-dependent prodrugs. Extension of this approach may enable synthesis of prodrugs for targeted therapies that spare normal tissue, further improving their therapeutic windows."

Journal • Oncology • CDK1

ROS-sensitive nanocarriers for synergistic X-PDT/chemo/immunotherapy of triple-negative breast cancer and metastasis. (PubMed, Acta Biomater) - "Here, we engineered photosensitizer verteporfin (VP) and T-lymphokine-activated killer cell-originated protein kinase (TOPK) inhibitor OTS964-encapsulated polymeric nanocarriers (VP/OTS964@NPs) for effective tumor X-PDT, molecule-targeted therapy and inducing robust antitumor immunity for synergistic immunotherapy of low immunogenic breast tumors and their lung metastases when combined with PD-L1 blockade. By further activating antitumor immune responses, this strategy is designed to suppress the distant and metastatic breast tumors. Overall, this work provides both a nanodrug platform and a therapeutic strategy for the treatment of poorly immunogenic solid tumors."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

SF3B1 phosphorylation is an evolutionarily conserved step in spliceosome activation carried out by the divergent, OTS964-insensitive kinase CRK9 in trypanosomes. (PubMed, bioRxiv) - "Although CRK9 and CDK11 deviate from each other substantially, we show that CRK9 activity is required to maintain SF3B1 phosphorylation in vivo , CRK9 directly phosphorylates TP motifs in the SF3B1 NTD in vitro , and the TP motifs themselves are crucial for spliceosome activation, demonstrating evolutionary conservation of this essential splicing step. Contrary to CDK11 and human cells, CRK9 and trypanosomes were rather insensitive to OTS964, indicating potentially exploitable differences in their ATP-binding pockets."

Journal • CDK1 • CDK9 • SF3B1

CDK11 inhibition induces cytoplasmic p21WAF1 splice variant by p53 stabilisation and SF3B1 inactivation. (PubMed, Mol Oncol) - "We show that blocking CDK11 activity with the OTS964 inhibitor causes p53 stabilisation through MDM2 downregulation...We discovered an isoform similar to human p21L in murine cells, suggesting evolutionary conservation of CDKN1A alternative splicing. Our results uncover an unknown link between RNA splicing and proliferation control involving a novel isoform of a key cell cycle inhibitor."

Journal • Oncology • CDK1 • CDKN1A • MDM2 • PCNA • SF3B1

Cyclin-dependent Kinase 11: Cellular Functions and Potential Therapeutic Applications. (PubMed, ChemMedChem) - "Given its integral role in key cellular processes and its dysregulation in various diseases, CDK11 has emerged as a compelling therapeutic target. This review provides a comprehensive overview of the biological functions and regulatory mechanisms of CDK11, discusses its role in cancer, viral and neurodegenerative diseases, and highlights advances in the discovery and development of CDK11 inhibitors, including OTS964, which has expanded our understanding of the biological functions of CDK11 and its prospects as a cancer-specific vulnerability."

Journal • Alzheimer's Disease • CNS Disorders • Human Immunodeficiency Virus • Infectious Disease • Oncology • CDK1 • SF3B1

CDK11 Inhibition for Mycn-Driven High-Risk Neuroblastoma (ASPHO 2025) - "Using MYCN amplified and nonamplified cell lines of neuroblastoma, we tested a study drug, OTS964, a specific small molecule inhibitor of CDK11... CDK11 is a novel dependency in MYCN-amplified neuroblastoma. These studies show that inhibition of CDK11 depletes MYCN expression and exerts potent anti-tumor effect. Further work is required to assess how CDK11 inhibition might be incorporated into other treatments currently utilized in high-risk neuroblastoma patients such as chemotherapy, radiation, and immunotherapy."

IO biomarker • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • CDK1 • MYCN

Exploring site-specific activation of kinase inhibitors via AKR1C3-mediated prodrug strategy (AACR 2025) - "In this study, we designed prodrugs of the kinase inhibitor OTS964, a potent inhibitor of the pan-essential kinase CDK11, modeled after the AKR1C3-activated prodrug OBI3424. Subsequent in vitro assays demonstrated that these prodrugs retained comparable activity to the parent compound in cell viability, immunoblotting, and NanoBRET assays. This study introduces a promising strategy to enhance the therapeutic window of pan-essential kinase inhibitors by concentrating their effects in affected tissues while sparing normal cells."

Oncology • AKR1C3 • CDK1

Targeting CDK11 in high-risk B cell acute lymphoblastic leukemia (AACR 2025) - "Additionally, the new combination with OTS964 and navitoclax showed synergism. In future studies, we will investigate how CDK11 inhibition regulates splicing factors other than SF3B1."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BCL2L1 • BCL2L2 • CDK1 • MCL1 • SF3B1 • TP53

CDK11, a splicing-associated kinase regulating gene expression. (PubMed, Trends Cell Biol) - "This review outlines the evolution of CDK11 and SF3B1 and their emerging roles in splicing regulation. It also discusses how CDK11 and its inhibition affect transcription and cell cycle progression."

Journal • Review • CDK1 • SF3B1

SEPT9: From pan-cancer to lung squamous cell carcinoma. (PubMed, BMC Cancer) - "This is the first study to systematically analyze the role of SEPT9 in cancers and innovatively apply the mitotic spindle-associated model to LUSC, fully demonstrating its potential as a valuable biomarker for cancer screening and prognosis, and highlighting its application value in promoting immunotherapy and chemotherapy, particularly for LUSC."

IO biomarker • Journal • Pan tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • FAM83D • HSF1 • SEPTIN9