Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability.

08:00 EDT 15th April 2019 | BioPortfolio

Summary of "Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability."

PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathologic evidence of vascular injury.


Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804


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Medical and Biotech [MESH] Definitions

An enzyme that catalyzes the reaction between a purine nucleoside and orthophosphate to form a free purine plus ribose-5-phosphate. EC

A purine nucleoside that has hypoxanthine linked by the N9 nitrogen to the C1 carbon of ribose. It is an intermediate in the degradation of purines and purine nucleosides to uric acid and in pathways of purine salvage. It also occurs in the anticodon of certain transfer RNA molecules. (Dorland, 28th ed)

A highly poisonous compound that is an inhibitor of many metabolic processes, but has been shown to be an especially potent inhibitor of heme enzymes and hemeproteins. It is used in many industrial processes.

Purines with a RIBOSE attached that can be phosphorylated to PURINE NUCLEOTIDES.

A potent inhibitor of CYCLIN-DEPENDENT KINASES in G1 PHASE and S PHASE. In humans, aberrant expression of p57 is associated with various NEOPLASMS as well as with BECKWITH-WIEDEMANN SYNDROME.

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