Fibroblast Growth Factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, were discovered that inhibit FGFR1 kinase with IC50 values of 23 and 50 µM. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 µM. The core structures represent new structural motifs for FGFR1 kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek selectivity, and hit identification.

Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed by cancer cells and the antigen presenting dendritic cells in the tumor microenvironment (TME). Activation of IDO1 depletes tryptophan and produces kynurenine, which induces T cell anergy and suppresses tumor control by the immune system. When combined with an immune checkpoint inhibitor, IDO1 inhibitors have shown promising anticancer activity in preclinical tumor models as well as in early stage clinical trials. Areas covered: IDO1 inhibitors disclosed in the patent literature from 2013-2017 are categorized, when applicable, according to their structural similarity to the clinical development candidates indoximod and PF-06840003, navoximod, epacadostat, KHK2455 and aryl-1,2-diamines, and BMS-986205 among others, respectively. Representative structures and their IDO1 inhibitory activity are presented to highlight the novelty and activity. Finally, the reported cocrystal structures were analyzed to provide insights for inhibitor-enzyme interactions and guidance for the design and discovery of next generation inhibitors. Expert opinion: This review demonstrates that the structural diversity of new IDO1 inhibitors could be expanded via a number of approaches.

No abstract

Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase is being pursued with computational guidance. Extension of azine-containing inhibitors into the entrance channel between Lys103 and Glu138 has led to the discovery of potent and structurally novel derivatives including dimeric inhibitors in an NNRTI-linker-NNRTI motif.

Kinetic and mechanistic studies detailing the oxidation of substrates derived from the 20 natural amino acids by the ferryl complex [Fe(IV)(O)(N4Py)](2+) are described. Substrates of the general formula Ac-AA-NHtBu were treated with the ferryl complex under identical conditions ([Ac-AA-NHtBu] = 10 mM, [Fe] = 1 mM, 1:1 H(2)O/CH(3)CN), and pseudo-first-order rate constants were obtained. Relative rate constants calculated from these data illustrated the five most reactive substrates; in order of decreasing reactivity were those derived from Cys, Tyr, Trp, Met, and Gly. Second-order rate constants were determined for these substrates by varying substrate concentration under pseudo-first-order conditions. Substrates derived from the other natural amino acids did not display significant reactivity, accelerating decomposition of the ferryl complex at a rate less than 10 times that of the control reaction with no substrate added. Ferryl decomposition rates changed in D(2)O/CD(3)CN for the Cys, Tyr, and Trp substrates, giving deuterium kinetic isotope effects of 4.3, 29, and 5.2, respectively, consistent with electron-transfer, proton-transfer (Cys and Trp), or hydrogen atom abstraction (Tyr) mechanisms. Decomposition rates for [Fe(IV)(O)(N4Py)](2+) in the presence of the Met and Gly substrates were identical in H(2)O/CH(3)CN versus D(2)O/CD(3)CN solvents. A deuterium kinetic isotope effect of 4.8 was observed with the labeled substrate 2,2-d(2)-Ac-Gly-NHtBu, consistent with [Fe(IV)(O)(N4Py)](2+) abstracting an alpha-hydrogen atom from Ac-Gly-NHtBu and generating a glycyl radical. Abstraction of alpha-hydrogen atoms from amino acid substrates other than Gly and oxidation of side chains contained in the amino acids other than Cys, Tyr, Trp, and Met were slow by comparison.