Senexin B / Biocad, Senex Biotech - LARVOL DELTA

CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells. (PubMed, Cell Death Discov) - "Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (BCR-ABLi) are the mainstay of chronic myelogenous leukemia (CML) treatment...Dissecting the effects of pharmacological CDK8/19 inhibition on CML survival in response to BCR-ABLi, we found that a selective, non-toxic CDK8/19 inhibitor (CDK8/19i) Senexin B (SenB) and other CDK8/19i sensitized K562 cells to different BCR-ABLi via attenuation of cell cycle arrest...In contrast, IM-treated BCR-ABL-positive KU812 CML cells, which did not induce p27Kip1, readily died regardless of SenB treatment. Thus, CDK8/19i prevent the quiescence-mediated escape from BCR-ABLi-induced apoptosis, suggesting a strategy for avoiding the CML relapse."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • ANXA5 • BCR • CASP9

Inhibition of Cyclin-Dependent Kinases 8/19 Restricts Bacterial and Virus-Induced Inflammatory Responses in Monocytes. (PubMed, Viruses) - "Senexin B was able to prevent the induction of gene expression of proinflammatory cytokines in THP1 and U937 cell lines and in human peripheral blood-derived mononuclear cells. Moreover, Senexin B substantially reduced functional manifestations of inflammation, including clustering and chemokine-dependent migration of THP1 monocytes and human pulmonary fibroblasts (HPF)."

Journal • Infectious Disease • Inflammation • Influenza • Pneumonia • Respiratory Diseases • GLI2

Role of CDK8/19 inhibition in sensitization of chronic myelogenous leukemia cells to Bcr-Abl antagonists (EACR 2023) - "Selective inhibitors of Bcr-Abl (prototype – imatinib mesylate, IM, Gleevec®) cause a therapeutic effect in the treatment of the primary process...Senexin B (SenB) and SNX631 were used for selective inhibition of CDK8/19, to suppress Bcr-Abl – IM, dasatinib, nilotinib, PF-114.Results and DiscussionsIt was found that CDK8/19 inhibition by SenB alone does not have an antiproliferative effect on CML cells...These changes were not demonstrated in KU812, where neither SenB sensitization, nor changes in expression of CKIs and c-Myc level were detected.ConclusionInhibition of CDK8/19 helps to overcome the delay of the cell cycle caused by the Bcr-Abl antagonist in CML cells and increase the death of tumor cells. The absence of general toxicity of CDK8/19 inhibitors during prolonged treatment under experimental conditions allows us to recommend CDK8/19 inhibition with targeted therapy of Bcr-Abl-positive tumors in prospect."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • CASP9 • CDK9 • CDKN2C • MYC • STAT3

Transcriptional Reprogramming Regulates Tumor Cell Survival in Response to Ionizing Radiation: a Role of p53. (PubMed, Bull Exp Biol Med) - "Senexin B, a non-toxic selective inhibitor of cyclin-dependent protein kinases 8 and 19 (CDK8 and CDK19), in combination with γ-photon irradiation in doses of 2-10 Gy increased the death of colon adenocarcinoma cell line HCT116 (intact p53) in a logarithmically growing culture, which was accompanied by the prevention of cell cycle arrest and a decrease of "senescence" phenotype. The effect of senexin B in cells with intact p53 is similar to that of Tp53 gene knockout: irradiated HCT116p53KO cells passed through the interphase and died independently of senexin B. The inhibitor reduced the ability of cells to colony formation in response to irradiation; p53 status did not affect the effectiveness of the combination of radiation and senexin B. Thus, the CDK8/19 inhibitor senexin B increased cell sensitivity to radiotherapy by mechanisms dependent and independent of p53 status."

Journal • Tumor cell • Colon Cancer • Colorectal Adenocarcinoma • Gastrointestinal Cancer • Oncology • CDK9

CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs. (PubMed, Stem Cell Res Ther) - "Our findings suggest a new risk mitigation approach for cell therapy and advance our understanding of the β-cell differentiation mechanism."

Journal • Transplantation • TGFBR1

Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo. (PubMed, Proc Natl Acad Sci U S A) - "Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2 BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2 BrCa."

Journal • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • BTG2 • HER-2 • STAT1

A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics. (PubMed, J Med Chem) - "Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation using a novel tumor-based PD assay showed good oral bioavailability of Senexin C with a strong tumor-enrichment PK profile and tumor-PD marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability."

Journal • PK/PD data • Hematological Malignancies • Leukemia • Oncology

Preventing adaptive therapeutic resistance to CDK4/6 inhibition with CDK8/19 inhibitors (SABCS 2021) - "We have now tested if selective CDK8/19 inhibitors, Senexin B and SNX631, could prevent the development of Palbociclib resistance in ER-positive breast cancers. These results suggest specific mechanisms through which CDK8/19 inhibition prevents the development of adaptive resistance to Palbociclib. These in vitro findings are currently being investigated in vivo in an ER-positive breast cancer xenograft model."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • CDK9 • ER • HIF1A • RB1