Multiscale Nature of Thixotropy and Rheological Hysteresis in Attractive Colloidal Suspensions under Shear.

Colloids with short range attractions self-assemble into sample-spanning structures, whose dynamic nature results in a thermokinematic memory of the deformation history, also referred to as "thixotropy." Here, we study the origins of the thixotropic effect in these time- and rate-dependent materials by investigating hysteresis across different length scales: from particle-level local measurements of coordination number (microscale), to the appearance of density and velocity fluctuations (mesoscale), and up to the shear stress response to an imposed deformation (macroscale). The characteristic time constants at each scale become progressively shorter, and hysteretic effects become more significant as we increase the strength of the interparticle attraction.

Microstructural Rearrangements and their Rheological Implications in a Model Thixotropic Elastoviscoplastic Fluid.

We identify the sequence of microstructural changes that characterize the evolution of an attractive particulate gel under flow and discuss their implications on macroscopic rheology. Dissipative particle dynamics is used to monitor shear-driven evolution of a fabric tensor constructed from the ensemble spatial configuration of individual attractive constituents within the gel. By decomposing this tensor into isotropic and nonisotropic components we show that the average coordination number correlates directly with the flow curve of the shear stress versus shear rate, consistent with theoretical predictions for attractive systems.

Publisher's Note: Characterizing short-term stability for Boolean networks over any distribution of transfer functions [Phys. Rev. E 94, 012301 (2016)].

This corrects the article DOI: 10.1103/PhysRevE.94.

Characterizing short-term stability for Boolean networks over any distribution of transfer functions.

We present a characterization of short-term stability of Kauffman's NK (random) Boolean networks under arbitrary distributions of transfer functions. Given such a Boolean network where each transfer function is drawn from the same distribution, we present a formula that determines whether short-term chaos (damage spreading) will happen. Our main technical tool which enables the formal proof of this formula is the Fourier analysis of Boolean functions, which describes such functions as multilinear polynomials over the inputs.

Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors.

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.

Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status.

Purpose: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models.

Patients And Methods: Quizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML.

Transient exposure to quizartinib mediates sustained inhibition of FLT3 signaling while specifically inducing apoptosis in FLT3-activated leukemia cells.

Fms-like tyrosine kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML). FLT3-activating internal tandem duplication (ITD) mutations are found in approximately 30% of patients with AML and are associated with poor outcome in this patient population. Quizartinib (AC220) has previously been shown to be a potent and selective FLT3 inhibitor.

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases.

A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.

Discovery of highly potent and selective pan-Aurora kinase inhibitors with enhanced in vivo antitumor therapeutic index.

Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors.

CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity.

Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non-small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAF(V600E) (K(d) BRAF(V600E) = 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC(50) = 78 and 60 nmol/L).

Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E.

The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors.

Noncooperatively optimized tolerance: decentralized strategic optimization in complex systems.

We introduce noncooperatively optimized tolerance (NOT), a game theoretic generalization of highly optimized tolerance (HOT), which we illustrate in the forest fire framework. As the number of players increases, NOT retains features of HOT, such as robustness and self-dissimilar landscapes, but also develops features of self-organized criticality. The system retains considerable robustness even as it becomes fractured, due in part to emergent cooperation between players, and at the same time exhibits increasing resilience against changes in the environment, giving rise to intermediate regimes where the system is robust to a particular distribution of adverse events, yet not very fragile to changes.

Influence and dynamic behavior in random boolean networks.

We present a rigorous mathematical framework for analyzing dynamics of a broad class of boolean network models. We use this framework to provide the first formal proof of many of the standard critical transition results in boolean network analysis, and offer analogous characterizations for novel classes of random boolean networks. We show that some of the assumptions traditionally made in the more common mean-field analysis of boolean networks do not hold in general.

4-Quinazolinyloxy-diaryl ureas as novel BRAFV600E inhibitors.

Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.

Novel series of pyrrolotriazine analogs as highly potent pan-Aurora kinase inhibitors.

The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.

Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.

Interactions between kinases and small molecule inhibitors can be activation state dependent. A detailed understanding of inhibitor binding therefore requires characterizing interactions across multiple activation states. We have systematically explored the effects of ABL1 activation loop phosphorylation and PDGFR family autoinhibitory juxtamembrane domain docking on inhibitor binding affinity.

AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily.

Initial stage of spinodal decomposition in a rigid-rod system.

The initial stage of spinodal decomposition is investigated for a rigid-rod system. Spinodal decomposition proceeds through either of two mechanisms: (1) The randomly aligned rods rotate toward a common director with no inherent length scale. (2) The rods diffuse axially and segregate into regions of common alignment with a selected length scale [script-l].

Computation of the nonhomogeneous equilibrium states of a rigid-rod solution.

The nonhomogeneous equilibrium phase behavior of a solution of rigid rods is analyzed for a periodic one-dimensional system. Stable and unstable equilibrium solutions for the distribution function are computed as extrema of the free energy of the system expressed by the nonhomogeneous generalization of Onsager's [Ann. N.

An inhibitor of Bcl-2 family proteins induces regression of solid tumours.

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction.

Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.

Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines.

Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway.

Objective: Myocyte death occurs by necrosis and caspase-mediated apoptosis in the setting of myocardial infarction. In vitro studies suggest that caspase activation within myocytes causes contractile protein degradation without inducing cell death. Thus, caspase activation may evoke left ventricular remodeling through 2 independent processes post-myocardial infarction.

Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice.

Background: Although the occurrence of cardiac myocyte apoptosis during heart failure has been documented, its importance in pathogenesis is unknown. Transgenic mice with cardiac-restricted overexpression of Galpha(q) exhibit a lethal, peripartum cardiomyopathy accompanied by apoptosis. To test whether apoptosis is causally linked to heart failure, we assessed whether inhibiting this cell death would improve left ventricular function and survival in the Galpha(q) peripartum cardiomyopathy model.

A mechanistic role for cardiac myocyte apoptosis in heart failure.

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80-250 myocytes per 10(5) nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis.