Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1-6. Despite advances in treatment with immune checkpoint inhibitors7-10, there is an unmet need in the treatment of MSI cancers11-14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.

Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers.

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C.

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors. SIGNIFICANCE: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397.

Structure-Based and Property-Driven Optimization of N-Aryl Imidazoles toward Potent and Selective Oral RORγt Inhibitors.

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor absorption, distribution, metabolism, and excretion (ADME) properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents toward a polar, water-rich area of the protein. This highly lipophilicity-efficient modification ultimately led to the discovery of compound 14, a potent and selective inhibitor of RORγt with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.

Molecular diversity through gold catalysis with alkynes.

In this feature article we cover most recent efforts in gold-catalysed transformations, highlighting the wide molecular diversity that can be achieved, in particular with regard to the formation of C-C bonds. Mechanistic interpretations of some cyclisations are based on our own work on the skeletal rearrangement of 1,6-enynes.

[Choking phobia: care plan in children and adolescents]. / Fobia a tragar: plan de cuidados en la infancia y adolescencia.

Eating disorders are a common problem in childhood. Swallowing phobia is characterised by fear of choking on having consumed food, liquids or tablets. Although they are considered a minor disorder and have low prevalence, there has been an increase in its incidence in children and adolescents in the past few years. The analysis of four cases treated in our day hospital for this specific phobia provides an assessment and the care necessary for its treatment and solution, in collaboration with other professionals and the family. The importance of the role that nurses have in the treatment of this psychological disorder is emphasised, as well admission to Day Units, the correct application of the treatment plan, the establishment of robust and reliable links with the family and the patient, and the motivation for therapeutic change by the whole family. It is essential to include the disorder in the differential diagnosis of eating disorders in children, as well as knowledge of this by community workers, in order to establish adequate early treatment to improve therapeutic outcomes.

[Nursing intervention in the family treatment plan for anorexia nervosa]. / Intervención enfermera en el plan terapéutico familiar de la anorexia nerviosa.

One of the main nursing interventions in the treatment of eating disorders is family psycho-education, an essential aspect of mental health treatment. This article describes and analyses the difficulties families expressed in the performance of a treatment plan for patients hospitalised for anorexia nervosa (AN) in the adolescent Day Hospital of Mental Health, of the Corporació Sanitària Parc Taulí, during 2009. Data was also collected data on professional interventions, performed by the nurse assigned to this unit, in order to group and categorise them, and as an aid to nursing intervention. A total of 10 families of the 10 patients admitted with a diagnosis of AN were included in the study period. In all cases, the patients were young women who had received treatment before in an Outpatient Unit, with partial or no response to the treatment. The difficulties expressed by the families were grouped into five categories from content analysis: problems in preparing a balanced diet, problems as they are unable to handle the behaviour and emotions of the patient, problems because as there are no previous family eating habits, problems because there is no family control or supervision, and problems with the established guidelines. Specific individualised interventions are proposed for developing and promoting a nursing care plan, and assessing the results.

[Profile of adolescents with social withdrawal admitted to a partial hospitalization unit of Mental Health]. / Perfil de los adolescentes con retraimiento social ingresados en una Unidad de Hospitalización Parcial de Salud Mental.

OBJECTIVE: To analyse the general characteristics of teenagers admitted to the Day Care Unit who fulfilled the criteria of social withdrawal, in order to implement a specific action plan within the existing resources for adolescents. METHOD: In this retrospective descriptive observational study, data were collected from withdrawal adolescent teenagers admitted to the unit over the year 2008. The data analysed were personal variables, diagnostic assessment on discharge, IQ assessment and Scale for Assessment of Communication and Interaction Skills and truancy. RESULTS: Of the 76 adolescents admitted to the unit, a total of 33 teenagers with social isolation were included in this study (43%). They had an average age of 15 years, an equal distribution between sexes and with a stay in the Unit 33 days longer than the general population studied. The average intellectual quotient of the social isolation group did not exceed the lower zone of the Weschler Scale (<80), and they scored below 50 points in the Scale for Assessment of Communication and Interaction Skills. CONCLUSIONS: The present research has enabled us to quantify the withdrawal phenomenon and some of its characteristics in a sample of adolescents admitted to the unit, in order to develop an interdisciplinary treatment program that allows us to address social withdrawal using a more holistic and effective approach.

Stereoselective gold-catalyzed cycloaddition of functionalized ketoenynes: synthesis of (+)-orientalol F.

A stereoselective gold-catalyzed [2 + 2 + 2] cycloaddition of ketoenynes substituted at the propargylic position with OR groups has been applied for the synthesis of (+)-orientalol F and pubinernoid B.

The mechanistic puzzle of transition-metal-catalyzed skeletal rearrangements of enynes.

Three pathways actually compete in metal-catalyzed cyclizations of enynes in which the metal selectively activates the alkyne: an endocyclic process and two exo-cyclizations, one proceeding by anti attack of the alkene and a second one resulting in a syn addition. Although cyclobutenes may be formed in transition-metal-catalyzed cyclization of some enynes, particularly, 1,7-enynes, these compounds are not necessarily the intermediates in the skeletal rearrangement. Cyclobutenes are formed by ring expansion of syn-cyclopropyl metal-carbenes formed in the syn pathway.

Gold(I)-catalyzed intramolecular cyclopropanation of dienynes.

Gold(I) complexes are the most active catalysts for the biscyclopropanation of dienynes to form tetracyclic compounds. PtII and ZnII are also able to promote the biscyclopropanation, although less efficiently. The configurations obtained in all cases with the use of gold(I) catalysts can be explained by the pathway proceeding through anti cyclopropyl gold carbenes. Similar intermediates are most probably involved in reactions catalyzed by RuII and PtII. Two different cyclopropanation pathways have been found; they depend on the structures of the cyclopropyl gold carbenes (anti or syn) and the relative arrangements of the metal carbenes and the alkenes.

Gold(I)-catalyzed cyclizations of 1,6-enynes: alkoxycyclizations and exo/endo skeletal rearrangements.

Gold(I) complexes are the most active catalysts for alkoxy- or hydroxycyclization and for skeletal rearrangement reactions of 1,6-enynes. Intramolecular alkoxycyclizations also proceed efficiently in the presence of gold(I) catalysts. The first examples of the skeletal rearrangement of enynes by the endocyclic cyclization pathway are also documented. Iron(III) is also able to catalyze exo and endo skeletal rearrangements of 1,6-enynes, although the scope of this transformation is more limited. The gold(I)-catalyzed endocyclic cyclization proceeds by a mechanism different from those followed in the presence of PdII, HgII, or RhI catalysts.

Social class, family, and life-style factors associated with overweight and obesity among adults in Peruvian cities.

BACKGROUND: Overweight and obesity have reached epidemic proportions in Latin America. OBJECTIVE: The purpose of this study was to explore social and behavioral factors associated with obesity in Peruvian cities. DESIGN: Between 1998 and 2000 health examination surveys were conducted among adults in 1176 families identified in six cities. Stratified by social class, multistaged random sampling was used. Using body mass index (weight (kg)/height (m)(2)), men and women were classified into normal weight (BMI <25), overweight (BMI 25-29), or obese (BMI > or =30); abdominal circumference (> or =94 cm in men and > or =84 cm in women) further identified morbidity risk. Several demographic, social, and behavioral variables were collected following standardized procedures. RESULTS: Adjusting for age, 37% of women were categorized as normal weight, 40% overweight, and 23% obese; corresponding figures for men were 40, 44, and 16%. More developed cities, e.g., Lima, Arequipa, and Ica, had the largest prevalence of overweight and obesity for both men and women. Adjusted logistic models showed that BMI > or =25 was positively correlated with age; whereas, education was negatively associated, only among women. Other significant associated factors of overweight included city of residence, television viewing > or =4 h daily in women, and underestimation of body weight status. CONCLUSIONS: The study showed elevated rates of overweight across the income level spectrum. Factors such as urban development stage, income, education, and gender posed differential relationships with the risk of overweight and must be considered in designing future public health interventions. Underestimation of body weight status and sedentary behavior may also constitute specific areas of intervention.

Fobia a tragar: plan de cuidados en la infancia y adolescencia / Choking phobia: Care plan in Children and Adolescents

Las alteraciones alimentarias son un problema frecuente en la edad pediátrica. La fobia a tragar se caracteriza por miedo a atragantarse al ingerir comida, líquidos o pastillas. Aunque es un trastorno considerado menor y de baja prevalencia, en estos últimos años se ha observado un aumento de su incidencia en la etapa infantil y juvenil. En el análisis de 4 casos atendidos en nuestro hospital de día por esta fobia específica, se establece la valoración y los cuidados necesarios para su tratamiento y solución, en colaboración con los demás profesionales implicados y la familia. Es de destacar el importante rol que posee enfermería en el tratamiento de este trastorno psicológico, en los dispositivos de hospitalización parcial, para la correcta aplicación del plan terapéutico, el establecimiento de vínculos robustos y de confianza con la familia y el propio usuario, así como en la motivación para el cambio terapéutico por parte de todo el núcleo familiar. Es indispensable la inclusión del trastorno en el diagnóstico diferencial de los trastornos de alimentación en la infancia y su conocimiento por parte de los profesionales comunitarios, con la finalidad de poder establecer un adecuado tratamiento precoz que mejore los resultados terapéuticos (AU)

Eating disorders are a common problem in childhood. Swallowing phobia is characterised by fear of choking on having consumed food, liquids or tablets. Although they are considered a minor disorder and have low prevalence, there has been an increase in its incidence in children and adolescents in the past few years. The analysis of four cases treated in our day hospital for this specific phobia provides an assessment and the care necessary for its treatment and solution, in collaboration with other professionals and the family The importance of the role that nurses have in the treatment of this psychological disorder is emphasised, as well admission to Day Units, the correct application of the treatment plan, the establishment of robust and reliable links with the family and the patient, and the motivation for therapeutic change by the whole family. It is essential to include the disorder in the differential diagnosis of eating disorders in children, as well as knowledge of this by community workers, in order to establish adequate early treatment to improve therapeutic outcomes (AU)