ledipasvir and Breast-Neoplasms

Breast cancer resistance protein (ABCG2) is a human ATP-binding cassette (ABC) that plays a paramount role in multidrug resistance (MDR) in cancer therapy. The discovery of ABCG2 inhibitors could assist in designing unprecedented therapeutic strategies for cancer treatment. There is as yet no approved drug targeting ABCG2, although a large number of drug candidates have been clinically investigated. In this work, binding affinities of 181 drug candidates in clinical-trial or investigational stages as ABCG2 inhibitors were inspected using in silico techniques. Based on available experimental data, the performance of AutoDock4.2.6 software was first validated to predict the inhibitor-ABCG2 binding mode and affinity. Combined molecular docking calculations and molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations, were then performed to filter out the studied drug candidates. From the estimated docking scores and MM-GBSA binding energies, six auspicious drug candidates-namely, pibrentasvir, venetoclax, ledipasvir, avatrombopag, cobicistat, and revefenacin-exhibited auspicious binding energies with value < -70.0 kcal/mol. Interestingly, pibrentasvir, venetoclax, and ledipasvir were observed to show even higher binding affinities with the ABCG2 transporter with binding energies of < -80.0 kcal/mol over long MD simulations of 100 ns. The stabilities of these three promising candidates in complex with ABCG2 transporter were demonstrated by their energetics and structural analyses throughout the 100 ns MD simulations. The current study throws new light on pibrentasvir, venetoclax, and ledipasvir as curative options for multidrug resistant cancers by inhibiting ABCG2 transporter.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Benzimidazoles; Binding Sites; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Databases, Chemical; Drug Discovery; Drug Resistance, Neoplasm; Female; Fluorenes; Humans; Hydrogen Bonding; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasm Proteins; Protein Binding; Pyrrolidines; Sulfonamides; Thermodynamics

Data are sparse on treatment of chronic hepatitis C virus (HCV) in cancer patients. We evaluated the efficacy and safety of sofosbuvir-based therapy (SOFBT) in cancer patients.. Patients treated with SOFBT at our center during 2014-2017 were included in a prospective observational study. Efficacy [sustained virologic response at 12 weeks after the end of treatment (SVR12)], cancer-related outcomes and adverse events (AEs) were assessed.. We included 153 patients. Most were men (109; 71%), white (92; 60%), non-cirrhotic (105; 69%), and with HCV genotype 1 (110; 72%). The most common cancers were hepatocellular carcinoma (HCC) (27; 18%) and multiple myeloma (14; 9%). The overall SVR12 rate was 91% (128/141). SVR12 was 100% in patients treated with ledipasvir/sofosbuvir for 8 weeks. Of the 32 patients initially excluded from cancer clinical trials because of HCV, 27 (84%) were granted cancer therapy access after starting SOFBT. Six patients with indolent non-Hodgkin's lymphoma (NHL) received SOFBT without cancer treatment. Two achieved complete remission, one had partial remission, and two had stable cancer. Within 6 months after SOFBT, 5% (6/121) of patients in remission or with stable cancer, had progression or recurrence (two with HCC and one each with esophageal cancer, cholangiocarcinoma, NHL, and tonsillar cancer). No de novo HCCs occurred. AEs were most commonly grade 1-2 (90%).. SOFBT in HCV-infected cancer patients is effective and safe, may permit access to investigational cancer therapy expanding treatment options, may induce remission of NHL, and may be used for 8 weeks.

Topics: Aged; Antiviral Agents; Benzimidazoles; Breast Neoplasms; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Fluorenes; Head and Neck Neoplasms; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Interferons; Liver Neoplasms; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Neoplasms; Polyethylene Glycols; Prospective Studies; Pyrrolidines; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Valine