Examining independent and combined accuracy of embedded performance validity tests in the California Verbal Learning Test-II and Brief Visuospatial Memory Test-Revised for detecting invalid performance.

The California Verbal Learning Test-Second Edition (CVLT-II) Forced Choice Recognition (FC) and Brief Visuospatial Memory Test-Revised (BVMT-R) Recognition Discrimination Index (RD) are embedded performance validity tests (PVTs) assessing material-specific neuropsychological processes (i.e., verbal and visual memory, respectively). Prior research demonstrated the utility of these PVTs independently; however, no study has compared their diagnostic accuracy for identifying invalid performance relative to each other and in combination within a single sample. This cross-sectional study included an adult neuropsychiatric sample who underwent neuropsychological evaluation. Validity groups were determined via independent criterion PVT performance, and consisted of 103 participants with valid and 25 with invalid neurocognitive performance. FC and RD were not significantly correlated (r = .154), yet both differed between validity groups (ηp2 = .14-.19). Previously established FC (≤14) and RD (≤4) cutoffs evidenced 32-40% sensitivity/90-98% specificity, though receiver operating characteristic (ROC) analyses indicated a more liberal FC cutoff (≤15) was optimal. Logistic regression models utilizing both embedded PVTs indicated that FC did not significantly improve classification accuracy above and beyond RD. Results support the clinical utility of existing cutoffs for FC and RD for independently identifying invalid performance, though the latter showed relatively better ability to detect invalid performance when both are used together.

Design, Synthesis, and Structure-Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3-Kinase γ (PI3Kγ).

Phosphoinositide-3-kinase γ (PI3Kγ) is highly expressed in immune cells and promotes the production and migration of inflammatory mediators. The inhibition of PI3Kγ has been shown to repolarize the tumor immune microenvironment to a more inflammatory phenotype, thereby controlling immune suppression in cancer. Herein, we report the structure-based optimization of an early lead series of pyrazolopyrimidine isoindolinones, which culminated in the discovery of highly potent and isoform-selective PI3Kγ inhibitors with favorable drug-like properties. X-ray cocrystal structure analysis, molecular docking studies, and detailed structure-activity relationship investigations resulted in the identification of the optimal amide and isoindolinone substituents to achieve a desirable combination of potency, selectivity, and metabolic stability. Preliminary in vitro studies indicate that inhibition of PI3Kγ with compound 56 results in a significant immune response by increasing pro-inflammatory cytokine gene expression in M1 macrophages.

Neighborhood Ethnic Composition and Self-rated Health Among Chinese and Vietnamese American Immigrants.

Immigrants tend to live in areas with higher co-ethnic density, and the effect of neighborhood ethnic composition could be particularly salient for health. This study explored associations between neighborhood ethnic composition and self-rated health among Asian immigrants. We analyzed data collected at baseline from 670 Chinese and Vietnamese immigrants enrolled in a lifestyle intervention trial. Residential addresses were geocoded and combined with neighborhood socio-demographic profiles based on census data. We used generalized estimating equations to examine neighborhood ethnic composition and self-rated health. Independent of individual-level factors, living in neighborhoods more densely populated by whites was associated with poor/fair self-rated health. Neighborhood household income and density of participants' own ethnic group were not associated with poor/fair self-rated health. More research is warranted to disentangle reasons why Chinese and Vietnamese immigrants living in white-concentrated neighborhoods reported poorer self-rated health, including investigating effects of discrimination, relative deprivation, and availability of social resources.

Discovery of Potent and Selective 7-Azaindole Isoindolinone-Based PI3Kγ Inhibitors.

The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγ offers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγ inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγ inhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγ inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.

Discovery of Potent and Selective PI3Kγ Inhibitors.

The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the "selectivity" and "alkyl-induced" pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 µM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an "alkyl-induced" pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.

Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73.

CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.