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Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth
TLDR
PAK4-related pathways are defined, additional support for PAK4 as a therapeutic target with a unique combination of functions (apoptotic, cytoskeletal, cell-cycle), and a potent, orally available small-molecule PAK inhibitor with significant promise for the treatment of human cancers is identified. Expand
The conformation of hepatitis C virus NS3 proteinase with and without NS4A: a structural basis for the activation of the enzyme by its cofactor.
TLDR
A structural basis for improved substrate turnover and affinity that follows complexation of NS3P with its NS4A cofactor is observed. Expand
Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds.
TLDR
Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology. Expand
Discovery of pyrroloaminopyrazoles as novel PAK inhibitors.
TLDR
The efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo. Expand
Structure-based design of novel human Pin1 inhibitors (I).
TLDR
Without a viable lead from internal screenings, a series of novel Pin1 inhibitors were designed by interrogating and exploring a protein crystal structure of Pin1 by integrating SBDD and parallel chemistry approaches to create a more attractive lead series. Expand
Structure-based design of novel human Pin1 inhibitors (II).
TLDR
The initial loss in potency of carboxylate analogs was likely due to weaker charge-charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand-protein interactions inThe proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor. Expand
Structure-based design of novel human Pin1 inhibitors (III): optimizing affinity beyond the phosphate recognition pocket.
TLDR
The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Expand
Identification and characterization of a novel and functional murine Pin1 isoform.
TLDR
A novel murine Pin1 isoform (mPin1L) consisting of the WW domain and the PPIase domain is identified, providing insights into phenotypic consequences for Pin1-null mice and may facilitate future biological study and pharmacological development in mice. Expand
Abstract PR-2: Discovery of p21‐activated kinase inhibitor PF‐03758309
TLDR
The pharmacodynamic and antitumor effects of PF‐3758309 support its evaluation as an anticancer agent, and Broad kinase screening has demonstrated that this is a selective pan‐PAK inhibitor with potential additional activities (e.g. AMPK). Expand
TRAIL stabilization and cancer cell sensitization to its pro-apoptotic activity achieved through genetic fusion with arginine deiminase
TLDR
The fusion protein of TRAIL and arginine deiminase was efficacious in a number of cell lines and synergized with some standard of care drugs and was superior to rhTRAIL administered at the same molar amounts. Expand
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