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/)

Natural, non-natural and ent-14 beta-hydroxyandrostane derivatives closely related to the cardenolide and bufadienolide skeletons were readily available through highly diastereo-/enantioselective Diels-Alder reactions calling for high pressure or Lewis acid activation. Moreover, in the presence of (R)- or (S)-carvone as chiral dienophile, the Diels-Alder reaction took place under chemodivergent parallel kinetic resolution control. Based on experimental and DFT studies, reasonable mechanism insights were postulated to explain the concave/convex and endo/exo selectivities observed for the formation of the different Diels-Alder and Diels-Alder-Michael adducts.

Starting from a common polyfunctionalized bicyclo[3.2.1]octane-6,8-dione intermediate, a concise synthetic route to tricyclic cores found in quadrane, suberosane, cedrane and related sesquiterpenes was developed using a Morita-Baylis-Hillman intramolecular reaction as a key step.

The Brønsted/Lewis acid catalyzed reaction of α-alkyloxyamides tethered to α,β-unsaturated ketones (aldehydes) afforded exclusively polyfunctionalized 1,3-oxazines with high diastereoselectivities and in high yields.

Bicyclo[3.3.0]octan-1-ol (diquinane ring system), bicyclo[4.3.0]nonan-1-ol (hydrindane ring system), and bicyclo[4.4.0]decan-1-ol (decalin ring system) belong to the medium-sized rings family which represent important scaffolds of numerous natural products. Thus, the development of new routes leading to such scaffolds is of importance because such carbocycles are ubiquitous in numerous biologically active compounds. This short review will focus on the main approaches reported since 2000, leading to these bicyclic scaffolds with high diastereo- and/or enantioselectivities. 1 Introduction 2 Diastereoselective Approaches 3 Diastereo- and Enantioselective Catalytic Approaches 4 Conclusion

14 beta-Hydroxysteroids, especially 14 beta-hydroxyandrostane derivatives are closely related to the cardenolide skeletons. The latter were readily available through highly diastero/ enantioselective Diels-Alder (DA) reactions requiring high pressure or Lewis acid activation. Moreover, in the presence of (R)- or (S)-carvone as a chiral dienophile, the DA-reaction takes place under chemodivergent parallel kinetic resolution control affording highly enantiomerically enriched 14 beta-hydroxysteroid derivatives or the corresponding (ent)-14 beta-hydroxysteroid derivatives.