Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene’s compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.

We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess excellent physicochemical properties for transdermal administration. Compound 26 bound to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activated AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed high aqueous solubility of 1.3 g/L at pH 7.4, and an in silico model as well as a customized parallel artificial membrane permeability assay indicated good skin permeation. Indeed, when measuring skin permeation through excised human skin, an excellent flux of 2 μg/(cm(2)·h) was determined without any permeation enhancers. In a 2 week Hershberger model using castrated rats, the compound showed dose-dependent effects fully restoring skeletal muscle weight at 0.3 mg/kg/day after subcutaneous administration with high selectivity over prostate stimulation.

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Neptunia oleracea Lour (water mimosa) is an edible medicinal plant used in treating various diseases. According to Phytochemical and Ethnobotanical Databases, Neptunia oleracea Lour is used in curing earaches, dysentery, syphilis, and tumour. The present study was aimed at demonstrating the anticancer activity of the Neptunia oleracea Lour methanolic extract. The methanolic extract was isolated and its anti-proliferative activity was studied on haematological cancer cell lines. The activity of the extract was further evaluated using cell cycle analysis and apoptosis assays. The effect of the extract on c-Myc and PErk1/2 modulation was also evaluated.Neptunia oleracea Lour extract induced cell death in cancer cells while sparing normal cells. An increase in cleaved PARP and reduction in BCL-2 levels observed upon treatment. Neptunia oleracea causes reduction in c-Myc levels and pERK1/2 protein levels. Thus, our work highlights the methanolic extract of Neptunia oleracea Lour as a promising anti-cancer agent.