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Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol
No full textBiosynthesis of glycosylphosphatidylinositol (GPI) is required for anchoring proteins to the plasma membrane, and is essential for the integrity of the fungal cell wall. Here, we use a reporter gene-based screen in Saccharomyces cerevisiae for the discovery of antifungal inhibitors of GPI-anchoring of proteins, and identify the oligocyclopropyl-containing natural product jawsamycin (FR-900848) as a potent hit. The compound targets the catalytic subunit Spt14 (also referred to as Gpi3) of the fungal UDP-glycosyltransferase, the first step in GPI biosynthesis, with good selectivity over the human functional homolog PIG-A. Jawsamycin displays antifungal activity in vitro against several pathogenic fungi including Mucorales, and in vivo in a mouse model of invasive pulmonary mucormycosis due to Rhyzopus delemar infection. Our results provide a starting point for the development of Spt14 inhibitors for treatment of invasive fungal infections
Development of Immediate Release (IR) 3D-printed oral dosage forms with focus on industrial relevance
No full textPharmaceutical 3D-printing represents a potentially new dosing and manufacturing approach for the pharmaceutical industry, with unique opportunities for personalization of dosage strengths. Fused deposition modelling (FDM) is a 3D-printing technique, which presents advantages for decentralized on-site manufacturing in hospitals and pharmacies. This study presents industrially relevant development of formulations for filaments with the required mechanical properties to be 3D-printable and providing immediate release (IR) dosage forms using safe materials approved also for pediatric use. Hydroxypropyl-cellulose (HPC) SSL was chosen as hydrophilic polymer and caffeine with a load of 5-20% as thermally stable model drug. Poly-(vinyl pyrrolidone-vinyl acetate) copolymer (Kollidon VA64) and poly-(vinyl alcohol-polyethylene glycol) graft copolymer (Kollicoat IR) were additional water-soluble polymers tested in combination with HPC and xylitol and polyethylene glycol (PEG) 4000 were evaluated as hydrophilic plasticizers and PEG4000 and maltodextrin as pore formers. Formulations were hot-melt extruded using a scalable twin-screw extruder and 3D-printed into honeycomb geometry solid dosage forms with high (100%) and low (80%) infill density. Rapid or very rapid release was achieved via formulation selection and tablet design parameters. PEG4000 in combination with Kollidon VA64 demonstrated superior processability and significantly accelerated release properties of the matrix independently of infill density. Lowering caffeine content improved hot-melt extrusion processability for each formulation but prolonged dissolution. The use of Kollicoat IR resulted in superior mechanical properties of the manufactured filaments, with easy handling and successful 3D-printing for drug load of 5 to 20%. For most formulations, lowering infill density of 3D-printed tablets yielded faster drug dissolution in agreement with the literature. However, the extent of the infill density effect varied depending on formulation. Caffeine was present in stable crystalline state in 3D-printed tablets. Printing temperature appeared to be critical for drug dissolution in vitro. This wide-ranging excipient investigation epitomizes the beginning of a toolbox approach targeting FDM processability in combination with immediate release characteristics of personalized dosage forms
Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
No full textFolate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant
An amphiphilic polymer-supported strategy enables chemical transformations under anhydrous conditions for DNA-encoded library synthesis.
No full textDNA-encoded libraries have emerged as a powerful hit generation technology. Combining the power of combinatorial chemistry to enumerate large compound collections with the efficiency of affinity selection screening methods, the methodology makes it possible to interrogate vast chemical spaces against biological targets of pharmaceutical relevance. Thus, the organic chemistry transformations that can be deployed to the synthesis of encoded libraries play a crucial role in the identification of attractive medicinal chemistry starting points. Unfortunately, these transformations are mostly limited to water-compatible reactions so that the growing oligonucleotide tag can be accommodated. Herein, we describe the development of a catch-and-release methodology utilizing a cationic, amphiphilic PEG-based polymer to perform chemical transformations in the presence of DNA under anhydrous conditions. We demonstrate the usefulness of this approach by performing several challenging transformations on DNA-small molecule conjugates in pure organic solvents: the addition of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran, the synthesis of saturated heterocycles using the tin (Sn) amine protocol (SnAP) in dichloromethane and the photoreductive Iridium−Nickel dual-catalyzed decarboxylative cross coupling of carboxylic acids to DNA-conjugates aryl halides in multititer-plate format
Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts
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The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time
No full textThe concept of functional groups (FGs) - sets of connected atoms that determine the intrinsic reactivity of the parent molecule and in part are responsible for the overall properties of the molecule form a foundation within modern medicinal chemistry. In this article we analyze occurrences of various FGs in molecules described in the medicinal chemistry literature in the last 25 years and their development and utilization over time. The popularity of various FGs is not evolving randomly but they show clear patterns of use. Various factors influencing these patterns, including introduction of new synthetic methods, novel techniques and strategies applied in the drug discovery and better knowledge of molecular properties affecting success of development candidates are discussed
Machine learning guided association of adverse drug reactions with in vitro target-based pharmacology
No full textAdverse drug reactions (ADRs) are one of the leading causes of morbidity and mortality in health care. Understanding which drug targets are linked to ADRs can lead to the development of safer medicines. Here, we analyze in vitro secondary pharmacology of common (off) targets for 2134 marketed drugs. To associate these drugs with human ADRs, we utilized FDA Adverse Event Reports and developed random forest models that predict ADR occurrences from in vitro pharmacological profiles. By evaluating Gini importance scores of model features, we identify 250 target-ADR associations. Among these are established relations, such as the association of in vitro hERG binding with cardiac arrhythmias, which validate our machine learning approach. Evidence on bile acid metabolism supports our identification of associations between the Bile Salt Export Pump and renal, thyroid, lipid metabolism, skin, respiratory tract and central nervous system disorders. Unexpectedly, our model suggests PDE3 is associated with 44 ADRs, including congenital renal disorders. These associations provide a comprehensive resource to support drug development and human biology studies
PRECLINICAL EVALUATION OF THE SIMULTANEOUS INHIBITION OF MCL-1 AND BCL-2 WITH THE COMBINATION OF S63845 AND VENETOCLAX IN MULTIPLE MYELOMA
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Strategies for Identity Testing of Therapeutic Oligonucleotide Drug Substances and Drug Products
No full textA risk-based approach for routine identity testing of therapeutic oligonucleotide drug substances and drug products is described. Risk analysis of solid-phase oligonucleotide synthesis indicates that intact mass measurement is a powerful technique for confirming synthesis of the intended oligonucleotide. Further risk assessment suggests that the addition of a second, sequence-sensitive identity test, which relies on a comparison of some property of the sample to a reference standard of proven identity, results in a sufficient test of identity for most oligonucleotide drug substances and products. Alternative strategies for drug product identity testing are presented. The analysis creates a common way to communicate risk and should result in a harmonized approach to identity testing that avoids the unnecessary analytical burden associated with routine de novo
sequencing, without compromising quality or patient safety
Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions
No full textAlpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human α-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of α-synucleinopathy bears importance for mechanistic and preclinical-translational studies