RNA therapeutics represents a powerful strategy for diseases where other approaches have failed, especially given the recent successes of mRNA vaccines against the coronavirus disease 2019 (COVID-19) and small interfering (siRNA) therapeutics. However, further developments are still required to reduce toxicity, improve stability and biodistribution of mRNA-LNPs (lipid nanoparticles). Here, we show a rational combinatorial approach to select the best formulation based on a new cationic lipid molecule (IM21.7c), which includes an imidazolium polar head. The study allowed us to select the optimal 5 lipids composition for in vivo mRNA delivery. IM21.7c based mRNA-LNPs measuring less than 100 nm had high encapsulation efficiency, protected mRNA from degradation, and exhibited sustained release kinetics for effective in vitro transfection. Most interestingly the biodistribution was significantly different from other clinically approved LNPs, with increased targeting to the lung. Further studies are now required to expand the possible applications of these new molecules.

With the increased number of therapeutic rAAV candidates reaching the clinical trial pipe-line, there is demand for innovative technologies to improve process development and facilitate manufacturing scale-up for future commercialization. To this end, Polyplus-transfection has worked hand-in-hand with viral vector manufacturers to develop a transfection re-agent specifically for large scale manufacturing in suspension cell systems: FectoVIR ® -AAV. FectoVIR ® -AAV aims to improve rAAV manufacturing processes by boosting productivity, bringing flexibility and facilitating scalability. Here, we share preliminary data from Allergan Biologics’ recent evaluation of FectoVIR ® -AAV against their current AAV production platform. Analysis of physical titers revealed a 3-fold increase in both viral particles (VP) and viral genome (VG) per ml of cell culture when using FectoVIR ® -AAV transfection reagent compared to PEIpro ® .

Lung cancer is the leading cause of cancer‐related death worldwide. CDK4/Cyclin D kinase is a key cell cycle regulator and constitutes an attractive pharmacological target for development of anticancer therapeutics, in particular in KRAS‐mutant lung cancer. Although several ATP‐competitive inhibitors targeting protein kinases have been developed as anticancer therapeutics, including several recently FDA‐approved CDK4 inhibitors, these compounds suffer from limited efficacy, selectivity and toxicity due to their conventional mechanism of action. Alternative strategies to overcome limitations associated with conventional kinase inhibitors include targeting protein/protein interactions and conformational transitions which are essential for kinase activation.Using a CDK4‐specific conformational biosensor that discriminates against ATP‐pocket binding compounds and that we implemented to screen a small chemical compound library of original small molecule scaffolds, we identified and validated a druggable and patentable compound that tampers with CDK4 function. This compound inhibits Rb phosphorylation, blocks proliferation of several cancer cell lines, and does not bind the ATP pocket of CDK4 nor any of 456 other kinases. An ongoing hit‐optimization process led us to identify derivatives exhibiting greater anti‐proliferative activity than Abemaciclib or Palbociclib in the A549, KRAS‐mutated NSCLC cell line. Interestingly, these non‐ATP CDK4 inhibitors only have a cytostatic effect, and do not induce cytotoxicity even at high doses. Further studies aimed at characterizing the mechanism of action of this compound have highlighted an unexpected and atypical mechanism of inhibition targeting CDK4. Our compounds constitute attractive leads as next generation of CDK4‐specific inhibitors and lung cancer therapeutics.Support or Funding InformationThis work was supported by the SATT Connectus, Strasbourg France and awarded the 2019 Best Academic Project of MATWIN (https://matwin.fr/en/cdk4ppi‐awarded‐2019‐best‐academic‐project‐by‐the‐matwin‐international‐board/)

AbstractAn unprecedented co‐catalytic effect of the solvent nitro group and the B(C6F5)3 Broensted acid is discovered to allow the first direct azidation of O‐unprotected aliphatic alcohols in a catalytic manner.

A cocatalytic effect of nitro compounds is described for the B(C6F5)3·H2O catalyzed azidation of tertiary aliphatic alcohols, enabling catalyst turnover for the first time and with a broad range of substrates. Kinetic investigations into this surprising effect reveal that nitro compounds induce a switch from first order concentration dependence in Brønsted acid to second order concentration dependence in Brønsted acid and second order dependence in the nitro compounds. Kinetic, electronic, and spectroscopic evidence suggests that higher order hydrogen-bonded aggregates of nitro compounds and acids are the kinetically competent Brønsted acid catalysts. Specific weak H-bond accepting additives may offer a new general approach to accelerating Brønsted acid catalysis in solution.

The inability to decouple Lewis acid catalysis from undesirable Brønsted acid catalysed side reactions when water or other protic functional groups are necessarily present has forced chemists to choose between powerful but harsh catalysts or poor but mild ones, a dichotomy that restricts the substrate scope of dehydrative transformations such as the direct SN1 reaction of alcohols. A systematic survey of Lewis and Brønsted acids reveals that the strong non-hydrolyzable Lewis acid B(C6F5)3 leads to highly chemoselective alcohol substitution in the presence of acid-sensitive alkenes, protecting groups and other functional groups without the typical compromise in reaction rates, substrate scope and catalyst loading.

AbstractThe efficiency is enhanced by the monoligated Pd(0) complex.

An efficient microwave assisted one-pot synthesis of substituted 3-(phenylmethylene)isoindolin-1-ones is reported via a copper-free Sonogashira coupling and a regioselective 5-exo-dig cycloisomerization. This domino reaction was also extended to other related heterocycles.

An intramolecular palladium(0)-mediated ortho-arylation of phenols applied to the synthesis of various substituted aporphines is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated Pd(0) complexes. This methodology was extended to para-arylation of phenols and employed in the synthesis of the aporphine alkaloid (−)-lirinine.

An intramolecular palladium(0)-mediated α-arylation of ketones applied to the synthesis of various substituted tetracyclic indoles is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated Pd(0) complexes. This methodology was extended to double α-arylation of ketones using one-pot reactions with either simultaneous addition or sequential addition of two aryl halides for producing aryl substituted tetracyclic indoles.

ChemInformVolume 43, Issue 33 Heterocyclic Compounds ChemInform Abstract: Synthesis of Tetracyclic Indoles via Intramolecular α-Arylation of Ketones. Malik Hellal, Malik Hellal Lab. Drug Discovery Neurodegener., Brigham Women′s Hosp., Harvard Med. Sch., Cambridge, MA 02139, USASearch for more papers by this authorShambhavi Singh, Shambhavi Singh Lab. Drug Discovery Neurodegener., Brigham Women′s Hosp., Harvard Med. Sch., Cambridge, MA 02139, USASearch for more papers by this authorGregory D. Cuny, Gregory D. Cuny Lab. Drug Discovery Neurodegener., Brigham Women′s Hosp., Harvard Med. Sch., Cambridge, MA 02139, USASearch for more papers by this author Malik Hellal, Malik Hellal Lab. Drug Discovery Neurodegener., Brigham Women′s Hosp., Harvard Med. Sch., Cambridge, MA 02139, USASearch for more papers by this authorShambhavi Singh, Shambhavi Singh Lab. Drug Discovery Neurodegener., Brigham Women′s Hosp., Harvard Med. Sch., Cambridge, MA 02139, USASearch for more papers by this authorGregory D. Cuny, Gregory D. Cuny Lab. Drug Discovery Neurodegener., Brigham Women′s Hosp., Harvard Med. Sch., Cambridge, MA 02139, USASearch for more papers by this author First published: 19 July 2012 https://doi.org/10.1002/chin.201233133Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Malik Hellal, Shambhavi Singh, Gregory D. Cuny, Synthesis of Tetracyclic Indoles via Intramolecular .alpha.-Arylation of Ketones., J. Org. Chem., 2012, 77, 4123–4130. DOI: 10.1021/jo300052z; 10.1021/jo300052z CASPubMedWeb of Science®Google Scholar Volume43, Issue33August 14, 2012 ReferencesRelatedInformation