Isoform Selective Phosphoinositide 3-Kinase γ and δ Inhibitors and Their Therapeutic Potential

摘要

Phosphoinositide 3-kinases (PI3Ks) represent a family of dual specificity kinases that by acting as both lipid and protein kinases regulate numerous biological processes, including cell growth, differentiation, survival, proliferation, migration and metabolism. The availability of genetically modified mice has recently allowed the functional characterization of class I PI3Ks, which are the most well studied PI3Ks. Whereas PI3Kδ and PI3Kβ are ubiquitously expressed, PI3Kα and PI3Kδ are mainly restricted to leukocytes and represent key modulators of innate and adaptive immune responses. Therefore, PI3Kδ and PI3Kγ have become attractive drug targets for the treatment of disorders of both innate and adaptive immune system, causing inflammatory and allergic diseases. The lack of specificity, isoform selectivity and biopharmaceutical properties of the initially available pharmacological inhibitors have provided impetus to the development of novel compounds that, by exhibiting improved isoform selectivity, potency and pharmacokinetic profile, might be more safely employed. Here, we describe recently published patent specifications disclosing new PI3K inhibitors, with a main focus on compounds displaying some selectivity for PI3Kδ and γ isoforms and their potential therapeutic applications.