Alexander Richard Liam Cecil

Progress in the design and development of phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of chronic diseases.

Publisher Summary The phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases involved in the regulation of a network of signal transduction pathways that control a range of cellular processes. A number of ATP-competitive, small molecule PI3K inhibitors with distinct sub-type selectivity profiles have recently entered clinical trials. Progress in the design, development and clinical evaluation of these compounds is outlined in this chapter. PI3Ks are classified into four distinct sub-families – commonly referred to as classes I, II, III and IV – based upon their substrate specificities, primary sequences, modes of regulation, and domain structures. The chapter outlines the PI3K signaling pathway based on down-stream targets and functions. Targeting PI3Ks have produced therapeutic effects of small molecule inhibitors. Several compounds have successfully been approved for clinical development, and are currently in early stage clinical trials. The development of small molecule, ATP-competitive PI3K inhibitors, has emerged as an important therapeutic strategy in the treatment of cancer, cardiovascular diseases, and immune and inflammatory disorders. Significant progress has been made over recent years in the design and development of small molecule modulators of the PI3K/AKT/mTOR signalling axis, as evidenced by the growing level of clinical activity in this area. Based on the therapeutic promise, it is clear that the design of small molecule PI3K inhibitors will continue to play an important role in the future development of personalized medicines.

Progress in the Development of Small Molecule Therapeutics Targeting Th17 Cell Function for the Treatment of Immune-Inflammatory Diseases

Publisher Summary In addition to small molecule therapeutics, a number of biological therapies that regulate Th17 cell activity have been discovered over the past decade. Researchers at Schering Corp. have disclosed the identification of antibody- and antigen-binding fragment therapeutics that function as antagonists of interleukins (IL-23, IL-17A, and IL-17F) and have also developed antibodies to target the IL-17 receptor. Scientists at Celltech have developed IL-17-targeted antibodies for the treatment of MS. Genentech have also developed antibody therapies regulating Th17 cell function, while combinations of biological agents that target IL-17, IL-21 and IL-23 production have also been disclosed by researchers at Beth Israel Deaconess Medical Center. In addition, Amgen have disclosed the discovery of polypeptide-based therapeutics that target the IL-17 receptor, and scientists at the Japan Health Sciences Foundation have developed oligonucleotides that inhibit the production of IL-17 and reduce inflammation induced by IL-17 through inhibition of the expression of the IL-17 gene and the NR4A2 gene. Furthermore, researchers at CalTech have developed polysaccharide therapies that suppress Th17-induced inflammation in models of colonic inflammation, and also induce differentiation of IL-10 to produce regulatory T cells to suppress inflammation.