Search

The X-ray structure of the ternary complex of a calcineurin A, calcineurin B, FKBP12, and the FK506 has been determined and observed that immunophilin-immunosuppressant FKBP12-FK506 complex inhibit the dephosphorylation of the phosphatase active site on calcineurin A. The ternary complex represents the 3D structure of a Ser/Thr protein phosphatase.

One of the challenges for targeting B-Raf V600E with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf WT , as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the ‘DFG-in/αC-helix-out’ conformation (Type IIB) likely will exhibit improved selectivity for B-Raf V600E . To explore this hypothesis, we transformed Type IIA inhibitor ( 1 ) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4 – 6 ) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf V600E /B-Raf WT biochemical ( b S), cellular ( c S) selectivity, and the phospho-ERK activation ( p A). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf V600E selectivity. [ABSTRACT FROM AUTHOR]

Abstract: mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series. [Copyright &y& Elsevier]

Abstract: mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC50 of 0.41μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model. [Copyright &y& Elsevier]

Abstract: Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase. [Copyright &y& Elsevier]

Abstract: A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters. [Copyright &y& Elsevier]

We recently described the identification of an optimized α-ketoamide warhead for our series of HCV NS3·4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P2. These compounds show exceptional enzymatic and cellular potency given their relatively small size. The marked enhancement of activity of these 3-substituted proline derivatives relative to previously reported 4-hydroxyproline derivatives constitutes additional evidence for the importance of the S2 binding pocket as the defining pharmacophore for inhibition of the NS3·4A enzyme. [Copyright &y& Elsevier]

Tetrapeptide-based peptidomimetic compounds have been shown to effectively inhibit the hepatitis C virus NS3·4A protease without the need of a charged functionality. An aldehyde is used as a prototype reversible electrophilic warhead. The SAR of the P1 and P2 inhibitor positions is discussed. [Copyright &y& Elsevier]