Timing of changes in Alzheimer's disease plasma biomarkers as assessed by amyloid and tau PET clocks.

Plasma biomarkers for Alzheimer's disease (AD) are increasingly being used to assist in making an etiological diagnosis for cognitively impaired (CI) individuals or to identify cognitively unimpaired (CU) individuals with AD pathology who may be eligible for prevention trials. However, a better understanding of the timing of plasma biomarker changes is needed to optimize their use in clinical and research settings. The aim of this study was to evaluate the timing of change of key AD plasma biomarkers (Aβ42/Aβ40, p-tau217, p-tau181, GFAP and NfL) from six different companies, along with established AD biomarkers, using AD progression timelines based on amyloid and tau PET.

Head-to-head comparison of leading blood tests for Alzheimer's disease pathology.

Introduction: Blood tests have the potential to improve the accuracy of Alzheimer disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes.

Methods: Plasma samples from the Alzheimers Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix.

An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors.

Cnk1 (connector enhancer of kinase suppressor of Ras 1) is a pleckstrin homology (PH) domain-containing scaffold protein that increases the efficiency of Ras signaling pathways, imparting efficiency and specificity to the response of cell proliferation, survival, and migration. Mutated KRAS (mut-KRAS) is the most common proto-oncogenic event, occurring in approximately 25% of human cancers and has no effective treatment. In this study, we show that selective inhibition of Cnk1 blocks growth and Raf/Mek/Erk, Rho and RalA/B signaling in mut-KRAS lung and colon cancer cells with little effect on wild-type (wt)-KRAS cells.

Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells.

The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain.

From laptop to benchtop to bedside: structure-based drug design on protein targets.

As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting proteinligand and protein-protein interactions.

A critical assessment of combined ligand- and structure-based approaches to HERG channel blocker modeling.

Blockade of human ether-à-go-go related gene (hERG) channel prolongs the duration of the cardiac action potential and is a common reason for drug failure in preclinical safety trials. Therefore, it is of great importance to develop robust in silico tools to predict potential hERG blockers in the early stages of drug discovery and development. Herein we described comprehensive approaches to assess the discrimination of hERG-active and -inactive compounds by combining quantitative structure-activity relationship (QSAR) modeling, pharmacophore analysis, and molecular docking.

Development of sulfonamide AKT PH domain inhibitors.

Disruption of the phosphatidylinositol 3-kinase/AKT signaling pathway can lead to apoptosis in cancer cells. Previously we identified a lead sulfonamide that selectively bound to the pleckstrin homology (PH) domain of AKT and induced apoptosis when present at low micromolar concentrations. To examine the effects of structural modification, a set of sulfonamides related to the lead compound was designed, synthesized, and tested for binding to the expressed PH domain of AKT using a surface plasmon resonance-based competitive binding assay.

Recent development of anticancer therapeutics targeting Akt.

The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics.

Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor.

Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1.

Chain termination and inhibition of mammalian poly(A) polymerase by modified ATP analogues.

We report the inhibition of mammalian polyadenylation by the triphosphate derivatives of adenosine analogues, 8-chloroadenosine (8-Cl-Ado) and 8-aminoadenosine (8-amino-Ado), which are under preclinical and clinical investigations for the treatment of hematological malignancies. The nucleotide substrate specificity of bovine poly(A) polymerase (PAP) towards C8-modified ATP analogues was examined using primer extension assays. Radiolabeled RNA primers were incubated with bovine PAP, and in the absence of ATP, no primer extension was observed with 8-Cl-ATP, whereas 8-amino-ATP resulted in chain termination.

Computational modeling of novel inhibitors targeting the Akt pleckstrin homology domain.

Computational modeling continues to play an important role in novel therapeutics discovery and development. In this study, we have investigated the use of in silico approaches to develop inhibitors of the pleckstrin homology (PH) domain of AKT (protein kinase B). Various docking/scoring schemes have been evaluated, and the best combination was selected to study the system.

Development and evaluation of a new statistical model for structure-based high-throughput virtual screening.

We have developed a High-Performance Computing (HPC)-based molecular docking scheme, termed HiPCDock, for drug discovery and development. To improve the statistical significance of our screening results, a bioinformatics approach, motivated by a sequence alignment package BLAST, was implemented. The statistical model was validated with ten known Thymidine Kinase (TK) binders and the real inhibitors showed significant statistics, in terms of low probabilities and expectation values.

In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT.

The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. Several studies have shown that this pathway is constitutively activated in many different cancer types. The goal of this study was to discover novel compounds that bind to the pleckstrin homology (PH) domain of AKT, thereby inhibiting AKT activation.

Discovery of a novel class of AKT pleckstrin homology domain inhibitors.

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain.

A potentiometric titration method for the crystallization of drug-like organic molecules.

It is generally accepted, that crystalline solids representing a low energy polymorph should be selected for development of oral dosage forms. As a consequence, efficient and robust procedures are needed at an early stage during drug discovery to prepare crystals from drug-like organic molecules. In contrast to the use of supersaturated solutions, we present a potentiometric crystallization procedure where saturated solutions are prepared in a controlled manner by pH-titration.

Computational aqueous solubility prediction for drug-like compounds in congeneric series.

It was the aim of the present work to develop a quantitative structure-property relationship (QSPR) model for predicting the aqueous solubility of drug-like compounds in congeneric series. Lipophilicity combined with structural fragment information, fragmental based correction factors and congeneric series indices were used as descriptors for a principal component analysis (PCA) followed by multivariate partial least squares regression statistics (PLS). The derived PLS regression model for the prediction of solubility parameters was based on an in-house data set of 2473 drug-like compounds.