Advertisement

Topics

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.

Affiliation

Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804
Pages:

Links

DeepDyve research library

PubMed Articles [12047 Associated PubMed Articles listed on BioPortfolio]

Optimization of novel benzofuro3,2-bpyridin-2(1H)-one derivatives as dual inhibitors of BTK and PI3Kδ.

BTK and PI3Kδ play crucial roles in the progression of leukemia, and studies confirmed that the dual inhibition against BTK and PI3Kδ could provide superior anticancer agents to single targeted ther...

Dual PI3K-BRD4 Inhibitor SF1126 Inhibits Colorectal Cancer Cell Growth in Vitro and in Vivo.

Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are key oncogenic cascades in colorectal cancer (CRC). SF1126 is a novel and potent PI3K-BRD4 dual inhibitor.

Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents.

HDAC inhibitors and BRD4 inhibitors were considered to be potent anti-cancer agents. Recent studies have demonstrated that HDAC and BRD4 participate in the regulation of some signal paths like PI3K-AK...

PIK3CA in cancer: the past 30 years.

Almost thirty years ago, PI3K was discovered as a lipid kinase associated with certain oncoproteins. The first decade of research on PI3K saw the identification, purification and cloning of PI3Kα. Th...

Discovery of novel 7-aryl 7-deazapurine 3'-deoxy-ribofuranosyl nucleosides with potent activity against Trypanosoma cruzi.

Chagas disease is the leading cause of cardiac-related mortality in endemic Latin American countries. Trypanosoma cruzi, the disease-causing pathogen, is unable to synthesize purines de novo, necessit...

Clinical Trials [3769 Associated Clinical Trials listed on BioPortfolio]

K-BASKET, TAS-117, PI3K/AKT Gene Aberration

The phosphatidylinositol 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) signaling pathway is one of the most frequently aberrantly r...

Study of XL147 or XL765 in Combination With Letrozole in Subjects With Breast Cancer

Phase 1 of this study will evaluate the maximum tolerated dose (MTD) of XL147 when given in combination with letrozole (Femara) and of XL765 when given in combination with letrozole. After...

Pediatric MATCH: PI3K/mTOR Inhibitor LY3023414 in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations

This phase II trial studies how well PI3K/mTOR inhibitor LY3023414 works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with TSC or PI3K/MTOR mutati...

PI3K Inhibitor BKM120 and Docetaxel in Treating Patients With Advanced Solid Tumor That is Locally Advanced, Cannot Be Removed By Surgery, or Metastatic

This phase I trial studies the side effects and best dose of PI3K inhibitor BKM120 when given together with docetaxel in treating patients with advanced solid tumor that is locally advance...

Study of the Combination of BKM120 and Cisplatin or Carboplatin in Patients With Advanced Solid Tumors

PI3K signaling is a hallmark of many cancers. Subsets of cancers become dependent on PI3K pathway signaling as a result of mutations of the PIK3CA gene itself or of regulators of PI3K (e.g...

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 2.4.2.1.

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.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topic

Vascular
Vascular relates to blood vessels (Oxford Medical Dictionary) and can be used to describe the supply of blood, a disease affecting the blood vessels or molecules associated with these structures. For example, <!--LGfEGNT2Lhm-->atherosclerosis ...


Searches Linking to this Article