Discovery of Rogaratinib (BAY 1163877): a pan-FGFR Inhibitor.

Rogaratinib (BAY 1163877) is a highly potent and selective small-molecule pan-fibroblast growth factor receptor (FGFR) inhibitor (FGFR1-4) for oral application currently being investigated in phase 1 clinical trials for the treatment of cancer. In this publication, we report its discovery by de novo structure-based design and medicinal chemistry optimization together with its pharmacokinetic profile.

Discovery of substituted N-phenylbenzenesulphonamides as a novel class of non-nucleoside hepatitis C virus polymerase inhibitors.

The RNA-dependent RNA polymerase NS5B of the hepatitis C virus (HCV) has emerged as one of the key targets for antiviral drug discovery. Here we describe a novel non-nucleoside inhibitor (NNI) chemotype identified by screening: The substituted N-phenylbenzenesulphonamides (SPBS) which showed reversible inhibition of NS5B from HCV genotype 1b with IC(50) values up to 40 nM. Based on the decreased inhibitory activity against a recombinant NS5B protein carrying the mutation L419M or M423T we assumed that the SPBS inhibitors bind to the thumb site II which has already been described as the allosteric binding site for the NNI carboxy thiophene. The postulated binding site was consequently confirmed by solving two co-crystal structures of NS5B in complex with SPBS analogues at 2.3 and 2.2Å resolutions. The inhibitors are hydrogen-bonded to the main chain Ser476 and Tyr477 and to the side chain of Arg501. In addition, the inhibitors displayed van der Waals interactions with several residues of the hydrophobic binding pocket Leu419, Ile482, Leu497, Met423 and Trp528. Notably, the two SPBS analogues reported here revealed significant differences in addressing the NH-group of the main chain Tyr477 by hydrogen-bonds, water-mediated or directly, which provoked a shift of the carboxyphenyl group of the inhibitors towards the His475 position for the water-mediated binding mode. Interestingly, the differences observed in the binding mode led to a different cross resistance profile at positions M423 and I482. Using a panel of 38 individual NS5B proteins derived from different HCV genotypes, we could demonstrate inhibitory activity of the SPBS against polymerases from HCV genotypes 1a and 1b whereas the inhibitor class failed to inhibit any of the non-genotype 1 polymerases efficiently. Furthermore we demonstrated initial antiviral activity for SPBS against the subgenomic replicons of HCV genotypes 1a and 1b, respectively, and no considerable cytotoxic potential against a panel of ten different cell types.

Solid-phase synthesis of dysidiolide-derived protein phosphatase inhibitors.

Biologically active natural products can be regarded as evolutionary selected and biologically validated starting points in structural space for the development of compound libraries. For libraries designed and synthesized around a given natural product, a higher hit rate and the identification of biologically relevant hits can be expected, justifying a probably higher investment in the development of the corresponding syntheses. This approach requires the development of complex multistep reaction sequences on the solid phase. Employing the protein phosphatase Cdc25 inhibitor dysidiolide as an example, we demonstrate that this goal can be achieved successfully. The reaction sequences developed led to dysidiolide analogues in overall 8-12 linear steps with the longest sequence on the solid support amounting to up to 11 sequential transformations. The desired products were obtained in overall yields ranging from 6% to 27% and in multimilligram amounts starting from 100 mg of resin. The transformations applied include a variety of very different reaction types widely used in organic synthesis (i.e., an asymmetric cycloaddition employing a removable chiral auxiliary, different organometallic transformations, olefination reactions, different oxidation reactions, acidic hydrolyses, and a nucleophilic substitution). Biological investigation of the eight dysidiolide analogues synthesized showed that they inhibit Cdc25C in the low micromolar range with the IC(50) value varying by a factor of 20 and that they display considerable and differing biological activities in cytotoxicity assays employing different cancer cell lines.