Publications
2023
Discovery of potent and exquisitely selective inhibitors of kinase CK1 with tunable isoform selectivity. Němec, V.; Khirsariya, P.; Janovská, P.; Martín Moyano, P.; Maier, L.; Lesáková, P.; Kebková, P.; Gybel’, T.; Berger, B.-T.; Chaikuad, A.; Reinecke, M.; Küster, B.; Knapp, S.; Bryja, V.*; Paruch, K.*
Angew. Chem. Int. Ed. 2023, e202217532. DOI 10.1002/anie.202217532
Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly selective inhibitors of CK1a, d and e. Based on their optimal in vitro and in vivo profiles and their exclusive selectivity, MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms. At proper concentrations, MU1250 and MU1500 allow for specific targeting of CK1d or dual inhibition of CK1d/e in cells. The compound MU1742 also efficiently inhibits CK1a and, to our knowledge, represents the first potent and highly selective inhibitor of this enzyme. In addition, we demonstrate that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, e.g. p38α, as exemplified by the compound MU1299.
Convergent Assembly of the Tricyclic Labdane Core Enables Synthesis of Diverse Forskolin-like Molecules. Szczepanik, P. M.; Mikhaylov, A. A.; Hylse, O.; Kučera, R.; Daďová, P.; Nečas, M.; Kubala, L.; Paruch, K.; Švenda, J.*
Angew. Chem. Int. Ed. 2023, 62, e202213183.
We report a new synthetic strategy for the flexible preparation of forskolin-like molecules. The approach is different from the previously published works and employs a convergent assembly of the tricyclic labdane-type core from pre-functionalized cyclic building blocks. Stereoselective Michael addition enabled the fragment coupling with excellent control over three newly created contiguous stereocenters, all-carbon quaternary centers included. Silyl enol ether-promoted ring-opening metathesis paired with ring closure were the other key steps enabling concise assembly of the tricyclic core. Late-stage functionalization sequences transformed the tricyclic intermediates into a set of different forskolin-like molecules. The modular nature of the synthetic scheme described herein has the potential to become a general platform for the preparation of analogs of forskolin and other complex tricyclic labdanes.