Class II Phosphoinositide 3-Kinases as Novel Drug Targets

Abstract

The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases central to regulating a wide range of important intracellular processes. Despite the vast knowledge around class I PI3Ks, the class II PI3Ks have been neglected, seemingly only due to the chronology of their discovery. Here we focus on the cellular functions of the three class II PI3K isoforms, PI3KC2α, PI3KC2β, and PI3KC2γ, in different cell systems and underline the emerging importance of these enzymes in different physiological and pathological contexts. We provide an overview on the current development of class II PI3 kinase inhibitors and outline the potential use for such inhibitors. The field is in its infancy as compared to their class I counterparts. Nevertheless, recent advances in understanding the roles of class II PI3 kinases in different pathological contexts is leading to an increased interest in the development of specific inhibitors that can provide potential novel pharmacological tools.

PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress

“…In this regard, it is tempting to hypothesize that a specific mobilization of the PI3P-dependent autophagic program may directly participate in the PI3KC2α-mediated prevention of renal cysts formation 20 , highlighting the protective role of the autophagy and PC dialog in kidney epithelium homeostasis. PI3KC2α activity is known to be involved in many physiological processes beyond its role in kidney physiology, by notably controlling mast cells degranulation, angiogenesis, thrombosis and systemic glucose homeostasis (reviewed in 41 ). Whether shear-stress autophagy is a downstream effector of PI3KC2α in these activities remains to be investigated.…”

Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics

“…CC-223 ( 124 ): a potent, selective, and orally bioavailable mTOR inhibitor with IC 50 of 16 nM, >200-fold selectivity over the related PI3K-α 53 , 2. MLN1117 (Serabelisib; 125 ): selective p110α (a PI3K) inhibitor with an IC 50 of 15 nM 54 , and 3. XL388 ( 126 ): a highly potent ATP-competitive mTOR inhibitor with an IC 50 of 9.9 nM 55 which simultaneously inhibits both mTORC1 and mTORC2.…”

PI3K inhibitors in thrombosis and cardiovascular disease

“…Moon M. July 10, 2019; 274013; OC 78.3). Class II PI3K inhibition has also been proposed as a therapeutic approach in cancer and diabetes [165,166]. With most of our current understanding of Class II PI3K function in organismal physiology coming from mouse gene targeting, the ongoing development [127–129, 165] of selective Class II PI3K inhibitors as tools will allow an improved understanding of the intricate roles and regulation of these enzymes in humans, and provide a better perspective of whether they may be useful and viable therapeutic targets in human disease.…”

“…Class II PI3K inhibition has also been proposed as a therapeutic approach in cancer and diabetes [165,166]. With most of our current understanding of Class II PI3K function in organismal physiology coming from mouse gene targeting, the ongoing development [127–129, 165] of selective Class II PI3K inhibitors as tools will allow an improved understanding of the intricate roles and regulation of these enzymes in humans, and provide a better perspective of whether they may be useful and viable therapeutic targets in human disease. Similarly, given the defect in thrombosis observed with loss of VPS34 in platelets, without an impact on haemostasis, pharmacological inhibition of Class III PI3K has been proposed as a novel anti‐thrombotic approach [147,148], and may also be of benefit for cancer and diabetes [133, 167, 168].…”