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.

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.

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-1-pyrazol-4-yl)pyrazolo[1,5-]pyrimidin-5-yl]-2-[(1)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1-isoindol-1-one (, IC = 0.

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.

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).

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).