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EFMC: Trends in Medicinal Chemistry and Chemical Biology.
No full textGround-breaking research in disease biology and continuous efforts in method development have uncovered a range of potential new drug targets. Increasingly, the drug discovery process is informed by technologies involving chemical probes as tools. Applications for chemical probes comprise target identification and assessment, as well as the qualification of small molecules as chemical starting points and drug candidates. Progress in probe chemistry has opened the way to novel assay formats and pharmaceutical compound classes. The European Federation of Medicinal Chemistry and Chemical Biology (EFMC) has launched the Chemical Biology Initiative to advance science in the field of medicinal chemistry and chemical biology, while representing all members of this extended scientific community. This review provides an overview of the many important developments in the field of chemical biology that have happened at the lively interface of academic and industrial research
The importance of dissolution for orally inhaled drug products: pharmaceutical, regulatory, and clinical considerations.
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Sustainable synthesis of L-phenylalanine derivatives in continuous flow by immobilized phenyl ammonia lyase
No full textThe application of phenyl ammonia lyases for the amination of a variety of cinnamic acids has been shown to be a cost-efficient method to produce a variety of phenylalanine analogues. Nonetheless, as many other biocatalytic tools, the process intensification, especially due to the high equivalents of ammonia needed, and the cost-efficiency of the catalyst production and use have been key points to further prove their usefulness. Here, we investigated the use of previously characterized PALs (AvPAL and PbPAL) for the amination of a series of substituted cinnamic acids. To enhance the process scalability and the reusability of the catalyst, we investigated the use of covalent immobilization onto commercially available supports, creating a heterogeneous catalyst with good recovered activity (50%) and excellent stability. The immobilized enzyme was also incorporated in continuous flow for the synthesis of 3-methoxy-phenyl alanine and 4-nitro-phenylalanine, which allowed for shorter reaction times (20 mins of contact time) and excellent conversions (88 ± 4% and 89 ± 5%) respectively, which could be maintained over extended periods of time, up to 24h. This work exemplifies the advantages that the combination of enzyme catalysis with flow technologies can have not only in the reaction kinetics, but also in the productivity, catalyst reusability and downstream processing
Rational Chemical Design of Molecular Glue Degraders
No full textTargeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. To overcome this challenge, we sought to identify a transposable chemical handle that would convert protein-targeting ligands into molecular degraders of their corresponding targets. Using the CDK4/6 inhibitor Ribociclib as a prototype, we identified a covalent handle that, when appended to the exit vector of Ribociclib, induced the proteasome-mediated degradation of CDK4 in cancer cells. Further modification of our initial covalent scaffold led to an improved CDK4 degrader with the development of a but-2-ene, 1,4-dione (“fumarate”) handle that showed improved interactions with RNF126. Subsequent chemoproteomic profiling revealed interactions of the CDK4 degrader and the optimized fumarate handle with RNF126 as well as additional RING family E3 ligases. We then transplanted this covalent handle onto a diverse set of protein-targeting ligands to induce the degradation of BRD4, BCR-ABL and c-ABL, PDE5, AR and AR-V7, BTK, LRRK2, HDAC1/3, and SMARCA2/4. Our study undercovers a design strategy for converting protein-targeting ligands into covalent molecular glue degraders
Advanced process automation of a pharmaceutical continuous wet granulation line: Model Predictive Control from solid feeders to dryer
No full textPharmaceutical continuous manufacturing provides the appropriate tools (e.g. the understanding of process dynamics and appropriate and adaptable control strategy) in order to deal with Quality-by-Design expectations and even to the future smart manufacturing described by Quality-by-Control. Those tools form part of the given framework of the regulatory agencies led by an effective quality risk management. Soft sensors and model predictive control are stepping stones for more agile processes and increased robustness by keeping the quality attributes of the final drug product in their acceptable ranges and by mitigating undesired events. The implementation of a MPC control system on a pharmaceutical continuous manufacturing plant for the wet granulation process is described. The control objectives and strategy are presented as well as the selected variables, the models identification, the MPC performance and its specific tuning. MPCs have been applied successfully on two pharmaceutical drug product (Diclofenac and Paracetamol): an accurate control of the API content and of the LOD was achieved in order to produce a constant quality of tablets on both drug products. In addition, some of the process parameters have been identified as mandatory to be step tested for each change of drug product, leading to a simplified MPC implementation
Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.
No full textIdentifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets
Modeling of bioprocess pre-stages for optimization of perfusion profiles and increased process understanding.
No full textImproving bioprocess efficiency is important to reduce the current costs of biologics on the market, bring them faster to the market, and to improve the environmental footprint. The process intensification efforts were historically focused on the main stage, while intensification of pre-stages has started to gain attention only in the past decade. Performing bioprocess pre-stages in the perfusion mode is one of the most efficient options to achieve higher viable cell densities over traditional batch methods. While the perfusion-mode operation allows to reach higher viable cell densities, it also consumes large amount of medium, making it cost-intensive. The change of perfusion rate during a process (perfusion profile) determines how much medium is consumed, thereby running a process in optimal conditions is key to reduce medium consumption. However, the selection of the perfusion profile is often made empirically, without full understanding of bioprocess dynamics. This fact is hindering potential process improvements and means for cost reduction. In this study, we propose a process modeling approach to identify the optimal perfusion profile during bioprocess pre-stages. The developed process model was used internally during process development. We could reduce perfused medium volume by 25%-45% (project-dependent), while keeping the difference in the final cell within 5%-10% compared to the original settings. Additionally, the model helps to reduce the experimental workload by 30%-70% and to predict an optimal perfusion profile when process conditions need to be changed (e.g., higher seeding density, change of operating mode from batch to perfusion, etc.). This study demonstrates the potential of process modeling as a powerful tool for optimizing bioprocess pre-stages and thereby guiding process development, improving overall bioprocess efficiency, and reducing operational costs, while strongly reducing the need for wet-lab experiments
Calculation-Driven Regioselective Functionalization of the Imidazo[1,2-a]pyrazine Scaffold via Zinc and Magnesium Organometallic Intermediates
No full textStraightforward calculations such as determinations of pKa values and N-basicities have allowed the development of a set of organometallic reactions for the regioselective functionalization of the underexplored imidazo[1,2 a]pyrazine. Thus, regioselective metalations of 6 chloroimidazo[1,2-a]pyrazine using TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl) such as TMPMgCl∙LiCl and TMP2Zn∙2MgCl2∙2LiCl provided Zn- and Mg-intermediates, that after quenching with various electrophiles gave access to polyfunctionalized imidazopyrazine heterocycles. Additionally, the use of TMP2Zn∙2MgCl2∙2LiCl as base for the first metalation allowed an alternative regioselective metalation. Nucleophilic additions at position 8 as well as selective Negishi cross-couplings complete the set of methods for selectively decorating this heterocycle of the future
Biocatalysis in water or in non-conventional media? Adding the CO2 production for the debate.
No full textNothing is for free. Enzymatic reactions produce two primary waste streams, an organic fraction and the aqueous effluent. The management of the wastewater results crucial to reach biotransformations with low environmental impact, because less CO2 is produced when wastewater can be mildly treated
Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon
No full textThe design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4