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Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities.

ABSTRACT: The predominant expression of the ? and ? isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some success in developing PI3K? inhibitors, progress in developing selective inhibitors of PI3K? has been rather disappointing. This has prompted the search for alternative targets with which to modulate PI3K signaling specifically in the immune system. One such target is the SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1) which de-phosphorylates PI(3,4,5)P(3) at the D5 position of the inositol ring to create PI(3,4)P(2). In this article, we first describe the current state of PI3K isoform-selective inhibitor development. We then focus on the structure of SHIP-1 and its function in the immune system. Finally, we consider the current state of development of small molecule compounds that potently and selectively modulate SHIP activity and which offer novel opportunities to manipulate PI3K mediated signaling in the immune system.

SUBMITTER: Blunt MD

PROVIDER: S-EPMC3410520 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities.

Blunt Matthew D MD Ward Stephen G SG

Frontiers in immunology 20120802

The predominant expression of the γ and δ isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some success in developing PI3Kδ inhibitors, progress in developing selective inhibitors of PI3Kγ has been rather disappointing. This has prompted the search for alternative targets with which to modulate PI3K ...[more]

PMID: 22876243

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Project description:BackgroundPhosphoinositide lipid kinases (PIKs) generate specific phosphorylated variants of phosatidylinositols (PtdIns) that are critical for second messenger signaling and cellular membrane remodeling. Mammals have 19 PIK isoforms spread across three major families: the PtIns 3-kinases (PI3Ks), PtdIns 4-kinases (PI4Ks), and PtdIns-P (PIP) kinases (PIPKs). Other eukaryotes have fewer yet varying PIK complements. PIKs are also an important, emerging class of drug targets for many therapeutic areas including cancer, inflammatory and metabolic diseases and host-pathogen interactions. Here, we report the genomic occurrences and evolutionary relationships or phylogenomics of all three PIK families across major eukaryotic groups and suggest potential ramifications for drug discovery.ResultsOur analyses reveal four core eukaryotic PIKs which are type III PIK4A and PIK4B, and at least one homolog each from PI3K (possibly PIK3C3 as the ancestor) and PIP5K families. We also applied evolutionary analyses to PIK disease ontology and drug discovery. Mutated PIK3CA are known to be oncogenic and several inhibitors are in anti-cancer clinical trials. We found conservation of activating mutations of PIK3CA in paralogous isoforms suggesting specific functional constraints on these residues. By mapping published compound inhibition data (IC50s) onto a phylogeny of PI3Ks, type II PI4Ks and distantly related, MTOR, ATM, ATR and PRKDC kinases, we also show that compound polypharmacology corresponds to kinase evolutionary relationships. Finally, we extended the rationale for drugs targeting PIKs of malarial Plasmodium falciparum, and the parasites, Leishmania sp. and Trypanosoma sp. by identifying those PIKs highly divergent from human homologs.ConclusionOur phylogenomic analysis of PIKs provides new insights into the evolution of second messenger signaling. We postulate two waves of PIK diversification, the first in metazoans with a subsequent expansion in cold-blooded vertebrates that was post-emergence of Deutrostomia\Chordata but prior to the appearance of mammals. Reconstruction of the evolutionary relationships among these lipid kinases also adds to our understanding of their roles in various diseases and assists in their development as potential drug targets.

Dataset Information

Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities.

Publications

Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities.

Similar Datasets

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