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A Web Tool for Calculating Substituent Descriptors Compatible with Hammett Sigma Constants
No full textElectron donating or accepting power of organic substituents is an important parameter affecting many properties of parent molecules, most notably their reactivity and pKa of ionizable groups. These substituent properties are usually described by Hammett sigma constants obtained by measuring ionization of substituted benzoic acids. Although values of these constants have been measured for the most common functional groups, data for many important substituents are not available. Some time ago we reported a method to calculate substituent descriptors compatible with Hammett sigma constants using quantum chemically derived parameters. The present publication revisits the older study by applying more sophisticated methodology and a larger training data set, as well as introduces a free web tool allowing to calculate substituent descriptors compatible with Hammet sigma constants available at https://bitly.com/getsigmas
BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma.
No full textBromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM
Transition-Metal Free Allylic Fluorination of Acyclic Olefins
No full textone step allylic fluorination of alkenes is reported which furnishes the products in a
highly regioselective manner via allylic rearrangement. The reaction proceeds
efficiently under mild conditions with the use of trisubstituted alkenes as olefin partner
and Selectfluor as an electrophilic fluorinating agent without the need of any transitionmetal
catalyst or pre-functionalized substrate
Tesidolumab (LFG316) for treatment of C5-variant patients with paroxysmal nocturnal hemoglobinuria.
No full textNot available
Allylations of Aryl/Heteroaryl Ketones: Neat, Clean, and Green. Applications to Targets in the Pharma- and Nutraceutical Industries
No full textAromatic and heteroaromatic ketones bearing an α-methine proton can be deprotonated and mono-allylated in minutes in
the complete absence of an organic solvent to arrive at the corresponding products in high isolated yields. Applications to
synthetic targets including both MK-7 and MK-9, as well as coenzyme Q9 (CoQ9) utilizing this new technology are
documented
Minimizing Material Consumption in Flow Process Research and Development: A Novel Approach Toward Robust and Controlled Mixing of Reactants
No full textScarce availability of chemical starting materials is a crucial challenge in the development of flow chemical processes.
This is particularly important for organometallic reactions, which typically require high flow rates and hence high material
consumption, to generate sufficiently short mixing and residence times. To address this issue, micromixers that mix efficiently even at small Re numbers and that have a low tendency of clogging are necessary. Here, we propose the usage of microannular gear pumps as active mixers, which allow the reduction of material consumption by >10-fold while achieving fast mixing times for common organometallic reactions. This novel approach is benchmarked against several commercially available mixers with respect to the mixing time at low flow rates, showing that the gear pumps can achieve fast mixing (< 50 ms) even at <1 mL/min. To assess the crucially important factor of time to blockage in a consistent manner, a novel protocol is developed based on the controlled precipitation of lithium salts during the mixing process. This shows that the gear pump is significantly more robust than common mixers as operation can be maintained for over 2 h. Lastly, we highlight that the microannular gear pump approach allows the manipulation of mixing time at equal residence time, by tuning the rotation speed, thus allowing for characterization of the mixing sensitivity of reactions. Taken together, our multiparametric analysis of common mixing approaches highlights that the usage of microannular gear pumps for active mixing of fast organometallic reactions presents a powerful alternative able to address current limitations of organic process development
Predicting in vivo brain penetration using multitask graph neural networks
No full textThe blood-brain-barrier (BBB) is a semi-permeable interface, separating the central nervous system (CNS) from the blood stream. The physiological role of the BBB is to create a stable microenvironment for the CNS by tightly regulating the transport of molecules from the blood to the brain and vice versa. For early drug discovery teams, it can be critical to know if com-pounds are able to penetrate into the brain compartment. Generally, pre-clinical in vivo studies measuring the ratio of total and free brain and blood concentrations (Kp and Kpuu, respectively) are required to estimate the brain penetration potential of a new drug entitiy. In this work, we evaluated the performance of different machine learning approaches to predict Kp, using Novar-tis internal and publicly available experimental data. We investigated the benefit of including in vitro experimental data as auxiliary tasks in multitask graph neural network (MT-GNN) mod-els. We observed that MT-GNN models generally outperformed single-task (ST) learning ap-proaches, which were only trained on in vivo brain penetration data. The best performing MT-GNN regression model achieved a coefficient of determination (R2) of 0.42 on a prospective validation set and outperformed all tested ST models. Overall, models solely based on public data achieved lower performance on the prospective validation set compared to models built with internal data. However, the MT-GNN based upon literature data outperformed all litera-ture-based ST models, with a R2 of 0.31. Lastly, we observed that post hoc classification using a MT-GNN regression model outperformed a MT-GNN classification model, with Matthew’s correlation coefficient values of 0.66 and 0.44, respectively. Taken together, we show that the inclusion of the right auxiliary tasks improves the prediction of in vivo brain penetration using MT-GNNs
Use of Multi Attribute Method by mass spectrometry as a QC release and stability tool for biopharmaceuticals – Regulatory Considerations
No full textno abstrac
High-Intensity Pulsed Electromagnetic Field-Mediated Gene Electrotransfection In Vitro
No full textA high-intensity pulsed electromagnetic field (HI-PEMF) is a non-invasive and non-contact delivery method and may, as such, have an advantage over gene electrotransfer mediated by conventional electroporation using contact electrodes. Due to the limited number of in vitro studies in the field of gene electrotransfection by HI-PEMF, we designed experiments to investigate and demonstrate the feasibility of such a technique for the non-viral delivery of genetic material into cells in vitro. We first showed that HI-PEMF causes DNA adsorption to the membrane, a generally accepted prerequisite step for successful gene electrotransfection. We also showed that HI-PEMF can induce gene electrotransfection as the application of HI-PEMF increased the percentage of GFP-positive cells for two different combinations of pDNA size and concentration. Furthermore, by measuring the uptake of larger molecules, i.e., fluorescently labelled dextrans of three different sizes, we showed endocytosis to be a possible mechanism for introducing large molecules into cells by HI-PEM