Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11.

Scientism, Ethics and Evil: From Mens Rea to Cerebrum Reus.

Can criminology thrive on quantitative studies alone? Can evil be operationalized? Quantitative work may have, for the time being, supplanted common sense, personal experience and resulting in an improbable "Periodic Table of humanity". Has the construction of the psychopathic concept surpassed positivist "constitutional" formulations and translated into effective (re)habilitation of individuals lacking affiliative ethical behaviors? Or has it simply fueled a deterministic neo-Lombrosian truism: moral development has a brain. Has it helped so far? Has letting go of fundamental moral concepts, implicit in organized religion - but pervasive in most cultures irrespective of religious affiliation and devotion - in favor of causal explanations based solely on neuroimaging, personality inventories or structured emotional decoding tasks, made a difference in the life - or in the defense for that matter - of wrongdoers diagnosed as intrinsically evil?

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest.

Scaffold Morphing Identifies 3-Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT).

Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy.

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors.

Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1. This Letter describes SAR exploration focused on improving both the and metabolic stability of the compounds, leading to the identification of as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents.

Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen.

Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design.

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway.

Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest.

The Dangers of Posthumous Diagnoses and the Unintended Consequences of Facile Associations: Jeffrey Dahmer and Autism Spectrum Disorders.

Posthumous diagnoses are not uncommonly given to notorious public and historical figures by applying retrospectively, and typically in the absence of the individual being diagnosed, contemporary diagnostic criteria. Although this may be relatively easy and free of consequences when it concerns clear-cut medical conditions, it may have unintended repercussions in the case of psychiatric disorders by creating myths and perpetuating stigma. The case of serial killer Jeffrey Dahmer is a typical example where a somewhat facile and almost syllogistic application of perhaps over-inclusive criteria may have contributed to the legend of solitary murderers as possibly suffering from an autism spectrum condition.

Externalizing and oppositional behaviors and karate-do: the way of crime prevention. A pilot study.

Childhood disruptive behaviors can be precursors to later deviance. To verify the efficacy of karate, a complex psychomotor activity that enhances self-regulation and executive skills, as an intervention for externalizing behaviors, 16 children, ranging in age from 8 to 10 years, and meeting diagnostic criteria for oppositional defiant disorder were studied. Eight were randomly assigned to a 10-month Wa Do Ryu karate program, whereas 8 children received no intervention.

Recognition of schematic facial displays of emotion in parents of children with autism.

Performance on an emotional labeling task in response to schematic facial patterns representing five basic emotions without the concurrent presentation of a verbal category was investigated in 40 parents of children with autism and 40 matched controls. 'Autism fathers' performed worse than 'autism mothers', who performed worse than controls in decoding displays representing sadness or disgust. This indicates the need to include facial expression decoding tasks in genetic research of autism.

Depressive symptoms, sex, and risk for Alzheimer's disease.

Depression associates with increased risk for dementia and Alzheimer's disease (AD), although it is unclear whether it represents an actual risk factor or a prodrome. To determine the relative hazard of premorbid depressive symptomatology for development of dementia and AD, we studied risk for incident dementia and AD over a 14-year period in 1,357 community-dwelling men and women participating in the 40-year prospective Baltimore Longitudinal Study of Aging. Screening for depressive symptoms, comprehensive medical and neuropsychological evaluations were prospectively collected every 2 years.

Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients.

Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene.

Pharmacologic treatment of autism.

Autism is a chronic and lifelong pervasive developmental disorder for which there is yet no effective cure, and medical management remains a major challenge for clinicians. In spite of the possible similarities with conditions that have an established pharmacotherapy, and despite improvements in some associated "problematic behaviors" following the use of available medications, effective medical treatment for the core symptoms involving language and social cognition remains elusive. The purpose of the present article is to review current biologic knowledge about autism in an attempt to correlate clinical trials with known mechanisms of disease.

Pervasive developmental disorders, psychiatric comorbidities, and the law.

Scattered reports propose that pervasive developmental disorders (PDDs) are risk factors for criminal behavior, yet the association between PDD and delinquent behavior is untrue for the majority of patients. However, individuals with PDDs may be at risk for legal trouble in the presence of comorbid psychopathology, and not solely on the basis of their developmental disability. This article analyzes theoretically the relationship between complex developmental disorders and delinquency with the hypothesis that the delinquent behaviors reported in it resulted from comorbid psychopathology and not as a direct consequence of a developmental disorder.

Methylenetetrahydrofolate reductase and angiotensin converting enzyme gene polymorphisms in two genetically and diagnostically distinct cohort of Alzheimer patients.

The role of methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE) gene polymorphisms as risk factors for the occurrence of Alzheimer's disease (AD) is still controversial. In this study, we investigated the common MTHFR C677-->T and ACE insertion/deletion (I/D) gene polymorphisms as risk factors for AD in two genetically and diagnostically distinct cohort of Alzheimer's patients. We analyzed a neuropathologically confirmed American cohort of 124 AD patients and 97 elderly controls, and a clinically diagnosed Italian cohort of 126 probable AD cases, 106 elderly controls, and a community-based sample of 1232 subjects aged under 65 years.

Preventing filicide in families with autistic children.

Autism is a complex neurodevelopmental disorder that affects social behaviors and parent-child interaction. It has been associated with an increased risk of social victimization, and a recent rise in number of acts of filicide of developmentally disabled children has included several cases of autism. In this article, possible risk factors for filicidal behavior in families with autistic children and prevention strategies are reviewed.

Repetitive behaviors in autistic disorder.

Introduction: Repetitive behaviors are common in autistic disorder, as in other developmental disabilities. Behaviors as diverse as stereotypies, cognitive inflexibility, and a need for sameness are grouped together under DSM IV classification, even though they are diverse in phenomenology, underlying neural circuitry, and possible clinical significance. In order to better define repetitive behaviors, we studied the relationship between such behaviors and chronological age, developmental level, estimated IQ, presumed mood state, severity of illness, as well as behavior reactivity to environmental stimuli, in a group of 121 consecutive autistic children, aged 2-4 and 7-11 years.

Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent, selective, and orally active human dopamine D4 receptor antagonists.

A new class of potent dopamine D(4) antagonists was discovered with selectivity over dopamine D(2) and the alpha-1 adrenoceptor. The lead compound was discovered by screening our compound collection. The structure-activity relationships of substituted isoindoline rings and the chirality about the hydroxymethyl side chain were explored.