Michael Flagella

TL;DR: A role for LRRK2 in regulating lysosome-related lamellar bodies is suggested and pulmonary toxicity may be a critical safety liability for L RRK2 kinase inhibitors in patients.

TL;DR: Effective incorporation of property and structure-based drug design guidelines into the molecular design process resulted in the discovery of small molecule inhibitors such as GNE-7915 and 19, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species.

TL;DR: Structurally diverse small molecule inhibitors suitable for assessing the implications of sustained in vivo LRRK2 inhibition are disclosed and structural modifications in the solvent-exposed region of the ATP-binding site are engineer that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities.

TL;DR: A series of potent and selective benzimidazole-based inhibitors of PI3Kδ are identified using a structure-based design approach and the pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.

TL;DR: GNE-900, an ATP-competitive, selective, and orally bioavailable ChK1 inhibitor, is described, which has little single-agent activity in the absence of chemotherapy and does not grossly potentiate the cytotoxicity of gemcitabine in normal bone marrow cells.