Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kd is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kdg inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lym-phocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kdg inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC-and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kdg engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kd inhibitors, LL-00 084282 showed su-perior and potent anticancer activity in both ABC-and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kdg inhibitor for further clinical evaluation in DLBCL patients. (c) 2022 Elsevier Inc. All rights reserved.

PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kβ as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with ∼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.

Diabetic retinopathy happens when there are high blood pressure and high sugar level in the body that damages the blood vessels and veins in retina. These arteries can become swollen and leaky, or they may close, block the flow of blood. Sometimes new, unusual blood arteries grow in the retina part. These unconditional changes can steal your eyesight. Manual examination and analysis of fundus images to detect morphological changes in the eyes are very sluggish and tedious. In the current scenario, deep learning has been set up as the most popular approach with superior performance in various areas and over traditional machine learning methods, especially in image analysis and treatment. In this paper, we adhere to traditional strategies mainly containing input Data acquisition, pre-data processing, segmentation and data preparation, feature measurement, feature extraction, model creation, model training, model testing on testing data, and outcome and analysis of the model. We have reviewed various algorithms and their challenges that help in the diagnosis of methods used in the detection of diabetic retinopathy.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.