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Journal ArticleDOI

Research advances on selective phosphatidylinositol 3 kinase δ (PI3Kδ) inhibitors.

Jiajia Sun1, Yifan Feng1, Yuan Huang1, San-Qi Zhang1, Minhang Xin1 
01 Oct 2020-Bioorganic & Medicinal Chemistry Letters (Pergamon)-Vol. 30, Iss: 19, pp 127457
TL;DR: This review summarizes research advances in varying chemical classes of selective PI3Kδ inhibitors and the structure-activity relationship and will mainly focus on the propeller- versus flat-type class of inhibitors.
About: This article is published in Bioorganic & Medicinal Chemistry Letters.The article was published on 2020-10-01. It has received 6 citations till now. The article focuses on the topics: Cell signaling & Kinase.
Citations
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Journal ArticleDOI
TL;DR: In this paper, the PI3K/AKT/mTOR signaling pathway plays a central role in regulating cell growth and proliferation and plays a key role in cell proliferation and cell survival.
Abstract: Introduction: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in regulating cell growth and proliferation and...

23 citations

Journal ArticleDOI
TL;DR: A comprehensive and general summary of numerous aminopyrimidines, their use as medicinal agents and their main anticancer activities can be found in this article, where the advances in organic and heterocyclic chemistry are considered in the targeted synthesis of aminoplyrimidine derivatives whose series contains the most demanded and efficient antitumor pharmaceuticals.

12 citations

Journal ArticleDOI
TL;DR: Based on indole scaffold, a potent and selective PI3K inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML) as discussed by the authors.

6 citations

Journal ArticleDOI
TL;DR: Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile and qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
Abstract: PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

6 citations

Journal ArticleDOI
TL;DR: In this paper , the authors present a survey of small molecule drugs capable of modulating the PI3K/PKB/mTOR signalling pathway, thus representing drugs or drug candidates to be used in the pharmacological treatment of different forms of cancer.
Abstract: The biochemical role of the PI3K/PKB/mTOR signalling pathway in cell-cycle regulation is now well known. During the onset and development of different forms of cancer it becomes overactive reducing apoptosis and allowing cell proliferation. Therefore, this pathway has become an important target for the treatment of various forms of malignant tumors, including breast cancer and follicular lymphoma. Recently, several more or less selective inhibitors targeting these proteins have been identified. In general, drugs that act on multiple targets within the entire pathway are more efficient than single targeting inhibitors. Multiple inhibitors exhibit high potency and limited drug resistance, resulting in promising anticancer agents. In this context, the present survey focuses on small molecule drugs capable of modulating the PI3K/PKB/mTOR signalling pathway, thus representing drugs or drug candidates to be used in the pharmacological treatment of different forms of cancer.

4 citations

References
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Journal ArticleDOI
TL;DR: Lapatinib plus capecitabine is superior to cape citabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.
Abstract: A b s t r ac t The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. Conclusions Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2- positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572.)

3,149 citations

Journal ArticleDOI
TL;DR: The potential of and challenges for the development of therapeutic agents that target this pathway in cancer are discussed and the potential and challenges in understanding of the PI3K pathway are highlighted.
Abstract: The phosphoinositide 3-kinase (PI3K) pathway is a key signal transduction system that links oncogenes and multiple receptor classes to many essential cellular functions, and is perhaps the most commonly activated signalling pathway in human cancer. This pathway therefore presents both an opportunity and a challenge for cancer therapy. Even as inhibitors that target PI3K isoforms and other major nodes in the pathway, including AKT and mammalian target of rapamycin (mTOR), reach clinical trials, major issues remain. Here, we highlight recent progress that has been made in our understanding of the PI3K pathway and discuss the potential of and challenges for the development of therapeutic agents that target this pathway in cancer.

2,315 citations

Journal ArticleDOI
TL;DR: Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.
Abstract: The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

1,396 citations

Journal ArticleDOI
19 May 2006-Cell
TL;DR: It is found that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110 alpha activity, which illustrates systematic target validation using a matrix of inhibitors that span a protein family.

1,152 citations

Journal ArticleDOI
TL;DR: Different PI3K isoforms generate specific lipids that bind to FYVE and pleckstrin homology domains in a variety of proteins, affecting their localization, conformation, and activities.

902 citations