A Novel Concept for Cleavable Linkers Applicable to Conjugation Chemistry - Design, Synthesis and Characterization.

Linkers with disulfide bonds are the only cleavable linkers that utilize physiological thiol gradients as a trigger to initiate the intracellular drug release cascade. Herein, we present a novel concept exploiting the thiol gradient phenomena to design a new class of cleavable linker with no disulfide bond. To support the concept, an electron-deficient sulfonamide-based cleavable linker amenable to conjugation of drug molecules with targeting agents, was developed.

Suppression of superoxide/hydrogen peroxide production at mitochondrial site I decreases fat accumulation, improves glucose tolerance and normalizes fasting insulin concentration in mice fed a high-fat diet.

We developed S1QEL1.719, a novel bioavailable S1QEL (suppressor of site I electron leak). S1QEL1.

Discovery of a Potent Chloroacetamide GPX4 Inhibitor with Bioavailability to Enable Target Engagement in Mice, a Potential Tool Compound for Inducing Ferroptosis .

Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified , a structural analog of the potent GPX4 inhibitor RSL3, that has much better plasma stability ( > 5 h in mouse plasma). The bioavailability of provided efficacious plasma drug concentrations with IP dosing, thus enabling studies to assess tolerability and efficacy.

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Guidelines on Model Fitting and Recommendations on Time Course for In Vitro Cytochrome P450 Induction Studies Including Impact on Drug Interaction Risk Assessment.

Translational and ADME Sciences Leadership Group Induction Working Group (IWG) presents an analysis on the time course for cytochrome P450 induction in primary human hepatocytes. Induction of CYP1A2, CYP2B6, and CYP3A4 was evaluated by seven IWG laboratories after incubation with prototypical inducers (omeprazole, phenobarbital, rifampicin, or efavirenz) for 6-72 hours. The effect of incubation duration and model-fitting approaches on induction parameters (E and EC) and drug-drug interaction (DDI) risk assessment was determined.

First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE-receptor E-type 4 (EP4), in patients with advanced cancers.

Background: E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046.

Methods: This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates.

Metabolic disposition of H3B-8800, an orally available small-molecule splicing modulator, in rats, monkeys, and humans.

H3B-8800, a novel orally available modulator of the SF3b complex, which potently and preferentially kills spliceosome-mutant tumor cells, is in clinical development for the treatment of advanced myeloid malignancies. We characterized the pharmacokinetics, metabolism and disposition of H3B-8800 in rats, monkeys and humans., H3B-8800 is a substrate of CYP3A4/5, flavin-containing monooxygenases (FMOs) and P-glycoprotein (P-gp), and showed a favorable drug-drug interaction profile as a perpetrator.

AWZ1066S, a highly specific anti- drug candidate for a short-course treatment of filariasis.

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, , using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome.

Celecoxib is a substrate of CYP2D6: Impact on celecoxib metabolism in individuals with CYP2C9*3 variants.

Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent K, K, and V of 67.2 μM, 12.

Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERα and ERα Breast Cancer.

Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation.

Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies: Focus on CYP3A4 mRNA In Vitro Response Thresholds, Variability, and Clinical Relevance.

The Innovation and Quality Induction Working Group presents an assessment of best practice for data interpretation of in vitro induction, specifically, response thresholds, variability, application of controls, and translation to clinical risk assessment with focus on CYP3A4 mRNA. Single concentration control data and Emax/EC data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary.

Pharmacokinetic/pharmacodynamic drug-drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs.

Aims: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers.

Methods: This was a three-part, open-label study.

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control.

The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines.

Impact of Probe Substrate Selection on Cytochrome P450 Reaction Phenotyping Using the Relative Activity Factor.

Accurately assessing the contribution of cytochrome P450 (P450) isoforms to overall metabolic clearance is important for prediction of clinical drug-drug interactions (DDIs). The relative activity factor (RAF) approach in P450 reaction phenotyping assumes that the interaction between P450-selective probes and testing systems is the same as the interaction of drug candidate with those systems. To test this assumption, an intersystem clearance ratio (ICR) was created to evaluate the difference in values between RAF-scaled intrinsic clearance (CL) and measured CL in human liver microsomes (HLMs).

KnowLife: a versatile approach for constructing a large knowledge graph for biomedical sciences.

Background: Biomedical knowledge bases (KB's) have become important assets in life sciences. Prior work on KB construction has three major limitations. First, most biomedical KBs are manually built and curated, and cannot keep up with the rate at which new findings are published.

eFIP: a tool for mining functional impact of phosphorylation from literature.

Technologies and experimental strategies have improved dramatically in the field of genomics and proteomics facilitating analysis of cellular and biochemical processes, as well as of proteins networks. Based on numerous such analyses, there has been a significant increase of publications in life sciences and biomedicine. In this respect, knowledge bases are struggling to cope with the literature volume and they may not be able to capture in detail certain aspects of proteins and genes.

Comprehensive defensin assay for saliva.

Defensins are highly basic cationic peptides that are important components of the innate and adaptive immune response pathways. In addition, these peptides are involved in CD8+ T cell response to HIV-1, increased pulmonary infection risk among cystic fibrosis patients, upregulated levels of HNP-5 for patients with ulcerative colitis and Crohn's disease, and monitoring HNP-3 levels as a tumor classification scheme for cutaneous T cell lymphomas, and have promise in the pharmaceutical field as a new class of antibiotics. Here we present a parallel assay for the alpha (HNP1-3) and beta (HBD1-2) classes of defensins in saliva that are naturally observed in the concentration range of 1 ng/mL to 10 microg/mL.