lexibulin (CYT997) / Gilead - LARVOL DELTA

CYT997 Induces Apoptosis in Hypertrophic Scar Fibroblasts and Inhibits Scar Formation. (PubMed, Eur J Pharmacol) - "It also regulated apoptosis-related proteins poly(ADP-ribose) polymerase (PARP) and caspase-3 in HSFs. These findings suggest that CYT997 has potential as a targeted therapy for hypertrophic scars by inducing apoptosis in HSFs and reducing fibrotic activity."

Journal • Fibrosis • Immunology • Oncology • CASP3

Identification and validation of microtubule depolymerizing agent, CYT997, as a potential drug candidate for hepatocellular carcinoma. (PubMed, Liver Int) - "CYT997 is a potentially efficacious and non-toxic drug candidate for HCC therapy. Its ability to down-regulate GPC3, β-catenin, and c-Myc highlights a novel mechanism of action."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CCNB1 • CDKN1A • CTNNB1 • GPC3 • MAP2K1 • MYC

Design, synthesis, and molecular docking study of novel cinnoline derivatives as potential inhibitors of tubulin polymerization. (PubMed, Z Naturforsch C J Biosci) - "Subsequently, molecular docking was performed to shed light on the putative binding mode of the newly synthesized cinnolines. The docking results indicate that these derivatives are potential inhibitors of tubulin polymerization and the best interaction was achieved with a computational ki = 0.5 nM and posed correctly over the lexibulin."

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Microtubule Polymerization Inhibition Enhances Human Hematopoietic Stem Cell Homing and Engraftment (ASH 2021) - "We concluded that treatment of CB CD34 + HSPCs for 16 hours with Lexibulin (Lex) or Vinblastine Sulfate (VS), both of which were microtubule polymerization (MP) inhibitors, could significantly promote the CD184 expression. Vinblastine Sulfate and Lexbulin were applied or registered as anti-cancer drugs for clinical use. Our study also indicates that MP inhibitors pretreatment of cells possesses significant translational implications, designating MP inhibitors as promising drug candidates to facilitate clinical HSCT."

Bone Marrow Transplantation • Obesity • Transplantation • CD34 • CXCL12 • CXCR4 • PRKDC • PTPRC • THY1

Predicting Drug Interactions with Human Equilibrative Nucleoside Transporters 1 and 2 Using Functional Knockout Cell Lines and Bayesian Modeling. (PubMed, Mol Pharmacol) - "Twenty-one compounds inhibited uridine uptake and abacavir, nevirapine, ticagrelor, and uridine triacetate had different IC values for ENT1 and ENT2...Clofarabine and cladribine were ENT1 and ENT2 substrates, while nevirapine and lexibulin were ENT1 and ENT2 non-transported inhibitors...Novel CRISPR/Cas9 functional knockouts of ENT1 and ENT2 in HeLa S3 cells were generated and characterized. Determining drug interactions with these transporters can be useful in identifying and predicting compounds that are ENT1 and ENT2 substrates, and can circumvent the blood-testis barrier through this transepithelial transport pathway in Sertoli cells."

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HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007). (PubMed, Adv Virol) - "Amongst the compounds tested, SRI-32007 (CYT997) demonstrated antiviral activity against HBV (genotype D) in HepG2.2.2.15 cell-based virus yield assay with 50% effective concentration (EC) and selectivity index (SI) of 60.1 nM and 7.2, respectively...Our experiments illustrate the utility of repurposing strategy to identify novel antiviral chemical leads. HBV core promoter inhibitors such as SRI-32007 might enable the development of novel therapeutic strategies to combat HBV infections."

Journal • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Oncology • Solid Tumor

Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer. (PubMed, J Exp Clin Cancer Res) - "CYT997 induces autophagy and apoptosis in gastric cancer by triggering mitochondrial ROS accumulation to silence JAK2/STAT3 pathway. CYT997 might be a potential antitumor drug candidate to treat GC."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Intracellular reduction in ATP levels contributes to CYT997-induced suppression of metastasis of head and neck squamous carcinoma. (PubMed, J Cell Mol Med) - "These findings support a critical role of ATP levels in cell invasion and metastasis under the influence of CYT997. Collectively, our data unveil the mechanism involved in mediating CYT997 action, and provide preclinical rationale for possible clinical application of CYT997 as a novel therapeutic strategy against aggressive HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity. (PubMed, J Hematol Oncol) - "Our findings demonstrate that blockage of Src augments the anticancer effect of CYT997 on prostate cancer and suggest that co-treatment of dasatinib and CYT997 may represent an effective therapeutic regimen for limiting prostate cancer."

Journal • Biosimilar • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Autophagy blockade sensitizes human head and neck squamous cell carcinoma towards CYT997 through enhancing excessively high reactive oxygen species-induced apoptosis. (PubMed, J Mol Med (Berl)) - "Blockade of autophagy by ATG7 depletion or addition of autophagy inhibitor hydroxychloroquine (HCQ) sensitizes HNSCC cells to CYT997 as evidenced by enhanced ROS-associated apoptosis. • Blockade of autophagy augments CYT997 efficacy by enhanced ROS-associated apoptosis. • Combination of autophagy inhibitors with CYT997 is more effective against HNSCC."

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Identification of molecular signatures and pathways to identify novel therapeutic targets in Alzheimer's disease: Insights from a systems biomedicine perspective. (PubMed, Genomics) - "Protein-drug interactions revealed 10 compounds that affect the identified AD candidate biomolecules, including anti-neoplastic agents (Vinorelbine, Vincristine, Vinblastine, Epothilone D, Epothilone B, CYT997, and ZEN-012), a dermatological (Podofilox) and an immunosuppressive agent (Colchicine). In the present study, it was identified blood-cell derived molecular signatures that might be useful as candidate peripheral biomarkers in AD. It was also identified potential drugs and epigenetic data associated with these molecules that may be useful in designing therapeutic approaches to ameliorate AD."

Biomarker • Journal

CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma. (PubMed, J Exp Clin Cancer Res) - "This study suggests that CYT997 induces apoptosis and autophagy in OS cells by triggering mutually enhanced ER stress and ROS and may thus be a promising agent against OS."

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