SNX-631 / Senex Biotech - LARVOL DELTA

Targeting Mediator Kinase Cyclin-Dependent Kinases 8/19 Potentiates Chemotherapeutic Responses, Reverses Tumor Growth, and Prolongs Survival from Ovarian Clear Cell Carcinoma. (PubMed, Cancers (Basel)) - "Therapeutically achievable doses of CDK8/19 inhibitors may provide clinical benefit for OCCC patients by inhibiting tumor growth and reversing platinum resistance, potentially addressing a critical treatment challenge in this rare ovarian cancer subtype."

Journal • Clear Cell Carcinoma • Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Solid Tumor

Targeting Mediator kinases CDK8/19 potentiates chemotherapeutic responses, reverses tumor growth, and prolongs survival from ovarian clear cell carcinoma (SGO 2024) - " A sub-IC50 concentration of SNX631 (500 nM) strongly potentiated effects of cisplatin, carboplatin, and paclitaxel in vitro after seven-days of exposure. CDK8/19i via SNX631 potentiates platinum responses in vitro and demonstrates strong in vivo antitumor effects, including tumor regression, when used as monotherapy and in combination with platinum-based therapy. This data suggests therapeutically achievable doses of SNX631-6 may provide clinical benefit, prevent tumorigenesis, and reverse and/or augment platinum resistance in patients with OCCC."

Oncology • Ovarian Cancer • CDK9

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

Dual therapeutic targeting of CDK8/19 and mTOR in triple negative breast cancer (SABCS 2022) - "Selective CDK8/19 inhibitor SNX631, when used as a single agent, inhibited the growth of several TNBC cell lines in vitro, cell-derived xenografts (CDXs) as well as patient derived xenografts (PDXs) in vivo, suggesting the potential of targeting CDK8/19 in treating TNBC. Significantly, the addition of a CDK8/19 inhibitor prevented the emergence of in vivo everolimus resistance both in CDX and PDX tumors upon treatment for up to 150 days, suggesting a potential for extending remission or even achieving cures in TNBC. Transcriptomic analysis demonstrated that this effect was due to the prevention of transcriptional reprogramming associated with everolimus resistance in tumor cells."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK9 • PTEN

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

Inhibition of CDK8/19 mediator kinase suppresses primary and metastatic growth of castration-resistant prostate cancer (AACR 2022) - "SNX631 also inhibited the growth of a CRPC PDX derived from a PCa patient who failed casodex, abiraterone, and docetaxel, in castrated mice. These results warrant the development of CDK8/19 inhibitors for the presently incurable metastatic CRPC. Funding acknowledgement: This research was funded by NIH grant R44CA203184 (M.C., I.R., M.L., Y.S.)"

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CDK9

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