Selective phosphoinositide 3-kinase inhibitors and implication in diabetic retinopathy as pharmacological tools

Phosphoinositide 3-kinases (PI3Ks) are ubiquitous enzymes, that regulate different cellular functions, most involved in pathogenesis and progression of several oncological diseases. Indeed, some PI3K inhibitors have been approved for blood cancers, such as lymphoma. Interestingly, leniolisib, a selective PI3Kδ kinase inhibitor, has been approved for the rare disease Activated Phosphoinositide 3-kinase Delta Syndrome (APDS). Activation of PI3K/AKT signaling is downstream to VEGF-A pro-angiogenic signaling, detrimental in diabetic retinopathy progression, a microvascular complication of diabetes mellitus. Recently, a report evidenced that inhibition of class IA PI3K (PI3Kδ) delivered beneficial effects in an in-vivo model of diabetic retinopathy. We hereby explored the implication of PI3K signaling in diabetic retinopathy. Moreover, we reviewed the current literature to highlight molecular features of class I PI3K selective inhibitors, to further guide the design of novel selective and safe drugs targeting PI3Kδ, for management of diabetic retinopathy or other retinal proliferative diseases.