Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy.

We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo.

Mexican consensus on cow's milk protein allergy.

Background: The aim of this study is to present the current views of a diverse group of experts on the diagnosis and treatment of Cow's Milk Protein Allergy (CMPA) in children under 2 years of age in Mexico.

Material And Methods: The study, led by a scientific committee of five experts in CMPA, was divided into six phases, including a modified Delphi process. A total of 20 panelists, all of whom were pediatric specialists, participated in administering a comprehensive 38-item questionnaire.

Isolation and Characterization of Monomeric Human RAD51: A Novel Tool for Investigating Homologous Recombination in Cancer.

DNA repair protein RAD51 is a key player in the homologous recombination pathway. Upon DNA damage, RAD51 is transported into the nucleus by BRCA2, where it can repair DNA double-strand breaks. Due to the structural complexity and dynamics, researchers have not yet clarified the mechanistic details of every step of RAD51 recruitment and DNA repair.

Design, Synthesis, and Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of Cancer.

CDC42 GTPases (RHOJ, CDC42, and RHOQ) are overexpressed in multiple tumor types and activate pathways critical for tumor growth, angiogenesis, and metastasis. Recently, we reported the discovery of a novel lead compound, ARN22089, which blocks the interaction of CDC42 GTPases with specific downstream effectors. ARN22089 blocks tumor growth in BRAF mutant mouse melanoma models and patient-derived xenografts (PDXs) .

Identification of RAD51-BRCA2 Inhibitors Using -Acylhydrazone-Based Dynamic Combinatorial Chemistry.

RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of -acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 -acylhydrazones.

Novel fragment-derived colchicine-site binders as microtubule-destabilizing agents.

Microtubules (MTs) are dynamic filaments of the cytoskeleton, which are formed by the polymerization of their building block tubulin. Perturbation of MT dynamics by MT-targeting agents (MTAs) leads to cell cycle arrest or cell death, a strategy that is pursued in chemotherapy. We recently performed a combined computational and crystallographic fragment screening approach and identified several tubulin-binding fragments.

Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action.

In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the α-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers.

Discovery and SAR Evolution of Pyrazole Azabicyclo[3.2.1]octane Sulfonamides as a Novel Class of Non-Covalent -Acylethanolamine-Hydrolyzing Acid Amidase (NAAA) Inhibitors for Oral Administration.

Inhibition of intracellular -acylethanolamine-hydrolyzing acid amidase (NAAA) activity is a promising approach to manage the inflammatory response under disabling conditions. In fact, NAAA inhibition preserves endogenous palmitoylethanolamide (PEA) from degradation, thus increasing and prolonging its anti-inflammatory and analgesic efficacy at the inflamed site. In the present work, we report the identification of a potent, systemically available, novel class of NAAA inhibitors, featuring a pyrazole azabicyclo[3.

Synthetic Lethality through the Lens of Medicinal Chemistry.

Personalized medicine and therapies represent the goal of modern medicine, as drug discovery strives to move away from one-cure-for-all and makes use of the various targets and biomarkers within differing disease areas. This approach, especially in oncology, is often undermined when the cells make use of alternative survival pathways. As such, acquired resistance is unfortunately common.

Novel, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II α over β.

We disclose a novel class of 6-amino-tetrahydroquinazoline derivatives that inhibit human topoisomerase II (topoII), a validated target of anticancer drugs. In contrast to topoII-targeted drugs currently in clinical use, these compounds do not act as topoII poisons that enhance enzyme-mediated DNA cleavage, a mechanism that is linked to the development of secondary leukemias. Instead, these tetrahydroquinazolines block the topoII function with no evidence of DNA intercalation.

Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders.

Aberrant expression ratio of Cl transporters, NKCC1 and KCC2, is implicated in several brain conditions. NKCC1 inhibition by the FDA-approved diuretic drug, bumetanide, rescues core symptoms in rodent models and/or clinical trials with patients. However, bumetanide has a strong diuretic effect due to inhibition of the kidney Cl transporter NKCC2, creating critical drug compliance issues and health concerns.

Reported patterns of pregnancy termination from Demographic and Health Surveys.

Introduction: Demographic and Health Surveys, widely used for estimation of fertility and reproductive health indicators in developing countries, remain underutilized for the study of pregnancy termination. This is partly due to most surveys not reporting the type of pregnancy termination, whether spontaneous or induced. Reproductive calendar data makes it possible to examine termination patterns according to contraceptive use at the time of pregnancy.

Surgical Infection after Posterolateral Lumbar Spine Arthrodesis: CT Analysis of Spinal Fusion.

Objective: To determine the incidence of infection after instrumented lumbar spine surgery, the demographic and surgical variables associated with acute infection, and the influence of infection and debridement on the consolidation of spinal fusion.

Methods: After obtaining approval from the hospital ethics committee, an observational study was made on a prospective cohort of consecutive patients surgically treated by posterolateral lumbar spine arthrodesis (n = 139, 2005-2011). In all cases, the minimum follow-up period was 18 months.

Pharmacophore Hybridization To Discover Novel Topoisomerase II Poisons with Promising Antiproliferative Activity.

We used a pharmacophore hybridization strategy to combine key structural elements of merbarone and etoposide and generated new type II topoisomerase (topoII) poisons. This first set of hybrid topoII poisons shows promising antiproliferative activity on human cancer cells, endorsing their further exploration for anticancer drug discovery.

Pharmacophore Identification and Scaffold Exploration to Discover Novel, Potent, and Chemically Stable Inhibitors of Acid Ceramidase in Melanoma Cells.

Acid ceramidase (AC) hydrolyzes ceramides, which are central lipid messengers for metabolism and signaling of sphingolipids. A growing body of evidence links deregulation of sphingolipids to several diseases, including cancer. Indeed, AC expression is abnormally high in melanoma cells.

Prevalence, incidence, and remission rates of urinary incontinence in women attended in gynecological practice.

Aims: To assess the prevalence of urinary incontinence (UI) in a cohort of women attended in primary care gynecological and estimate the incidence and remission rates of UI symptoms at 1 year.

Methods: We performed a multicenter prospective cohort study of women attending eight primary care gynecological practices. Consecutive women attended for gynecological issues different from UI were invited to participate in the study by answering the International Consultation on Incontinence questionnaire-Short Form (ICIQ-UI-SF).

Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies.

4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (3b) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b, and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak, a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b.

Intergenerational Transmission of Reproductive Traits in Spain during the Demographic Transition.

In this paper intergenerational dimensions of reproductive behavior are studied within the context of the experience of a mid-sized Spanish town just before and during the demographic transition. Different indicators of reproduction are used in bivariate and multivariate approaches. Fertility shows a small, often statistically significant intergenerational dimension, with stronger effects working through women and their mothers than those stemming from the families of their husbands.

Binding affinities of oligonucleotides and PNAs containing phenoxazine and G-clamp cytosine analogues are unusually sequence-dependent.

Melting temperatures of DNA duplexes containing the phenoxazine (P) and G-clamp (X) cytosine analogues exhibited a strong and unusual dependence on the nucleoside flanking the modified nucleobase, and the same trend was observed in PNA-DNA duplexes incorporating X in the PNA chain. Molecular dynamics simulations of the DNA duplexes show that generalized stacking (including secondary interactions of the ammonium group of X) and hydrogen bonding are good descriptors of the different duplex stabilities.

Flows of financial resources for health research and development in Brazil, 2000-2002.

Objective: To map and measure the flows of financial resources for health research and development in Brazil for the years 2000-2002.

Methods: After adapting the methodology developed for the Center for Economic Policy Research, data were collected on the sources and uses of resources for health research and development.

Results: The annual average value of resources apportioned to health research and development was approximately 573 million US dollars.

Synthesis of amino- and guanidino-G-clamp PNA monomers.

Syntheses of the protected amino- and guanidino-G-clamp PNA monomers, 9a and 9b, respectively, have been accomplished in eight steps from 5-bromouracil. Enhanced stacking interactions and additional hydrogen bonds with guanine should increase the affinity of PNAs incorporating these cytosine analogues for their complementary strands. [reaction: see text]