Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.

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.

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models.

PURPOSE: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates. EXPERIMENTAL DESIGN: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates. RESULTS: In a murine melanoma tumor model, the ratio of tumor-killing CD8(+) T cells to Foxp3(+) regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti-CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates. CONCLUSIONS: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies.

Antifertility activity of Artemisia vulgaris leaves on female Wistar rats.

AIM: To evaluate the antifertility activity of Artemisia vulgaris leaves on female Wistar rats. METHOD: The plant extract was tested for its effect on implant formation at two dose levels, 300 and 600 mg·kg⁻¹, respectively. The effective methanolic plant extract was further studied for estrogenic potency on ovariectomised immature female Wistar rats. RESULTS: The data presented in this study demonstrate the antifertility potential of Artemisia vulgaris methanolic leaf extract, which shows a strong and significant decrease in implant formation (100%), and a strong estrogenic effect resulting in a significant increase in uterine weight in immature ovariectomised rats. These observations suggest that the methanolic extract of Artemisia vulgaris leaves has strong anti-implantation activity and estrogenic activity. CONCLUSION: The methanolic plant extract of A. vulgaris has antifertility activity.

Neuroprotective and antioxidant potential of terpenoid fraction from Hygrophila auriculata against transient global cerebral ischemia in rats.

CONTEXT: The plant Hygrophila auriculata (K. Schum) Heine. (Acanthaceae) is widely used in the Indian System of Medicine as "Rasayana" for treating brain and liver diseases. OBJECTIVES: The present study evaluated the in vivo antioxidant and neuroprotective effect of aterpenoid rich fraction (TF) from Hygrophila auriculata in a rat model of transient global cerebral ischemia (tGCI). MATERIALS AND METHODS: Male Wistar rats were grouped as sham control, tGCI control, vitamin E (500 mg/kg) and TF (100 & 200 mg/kg) treated groups. Following 7 days of drug administration, animals were subjected to tGCI by permanent occlusion of both vertebral and transient occlusion of carotid arteries for 10 min followed by reperfusion. The neuroprotective effect was assessed by tGCI induced neurological, sensory motor deficit in rats. Brain antioxidants such as superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) were investigated. Further, a histopathological examination was done in CA1 hippocampus. RESULTS: tGCI induction resulted in an increase in beam balance score (5.1), number of entries in open field (131) and a decrease in time spent in rotorod (47 s). In contrast, TF treatment resulted in a significant decrease in (p < 0.01) beam balance score (2.9), number of entries (67) and increased time spent in rotorod (63.25 s). There was also a significant (p < 0.001) decrease in brain SOD and GSH with an increase in MDA. TF treatment resulted in restoration of antioxidants and protection of hippocampal CA1 neurons against tGCI insult. CONCLUSION: It is concluded that TF from Hygrophila auriculata shows neuroprotective potential against tGCI induced oxidative stress.