Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy

Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3‑Kinase δ for the Treatment of Respiratory Disease

Optimization of lead compound <b>1</b>, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates <b>2</b> (GSK2269557) and <b>3</b> (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds <b>2</b> and <b>3</b> are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3‑Kinase δ for the Treatment of Respiratory Disease

Optimization of lead compound <b>1</b>, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates <b>2</b> (GSK2269557) and <b>3</b> (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds <b>2</b> and <b>3</b> are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation