Discovery of selective phosphatidylinositol 3-kinase inhibitors to treat hematological malignancies

Zhu, Jingyu; Hou, Tingjun; Mao, Xinliang

doi:10.1016/j.drudis.2015.03.009

Cited by 47 publications

(24 citation statements)

References 56 publications

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“…• Idelalisib is a p110-d-specific inhibitor used in the treatment of chronic lymphocytic leukemia (Zhu et al, 2015). Several other isoform-selective class I PI3K inhibitors exist.…”

Section: And Action! Pi 3-phosphate-binding Modules and Effectorsmentioning

confidence: 99%

Phosphatidylinositol 3‐phosphates—at the interface between cell signalling and membrane traffic

2016

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Phosphoinositides (PIs) form a minor class of phospholipids with crucial functions in cell physiology, ranging from cell signalling and motility to a role as signposts of compartmental membrane identity. Phosphatidylinositol 3-phosphates are present at the plasma membrane and within the endolysosomal system, where they serve as key regulators of both cell signalling and of intracellular membrane traffic. Here, we provide an overview of the metabolic pathways that regulate cellular synthesis of PI 3-phosphates at distinct intracellular sites and discuss the mechanisms by which these lipids regulate cell signalling and membrane traffic. Finally, we provide a framework for how PI 3-phosphate metabolism is integrated into the cellular network.

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“…• Idelalisib is a p110-d-specific inhibitor used in the treatment of chronic lymphocytic leukemia (Zhu et al, 2015). Several other isoform-selective class I PI3K inhibitors exist.…”

Section: And Action! Pi 3-phosphate-binding Modules and Effectorsmentioning

confidence: 99%

Phosphatidylinositol 3‐phosphates—at the interface between cell signalling and membrane traffic

2016

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“…PI3K has received much attention in recent years as a target for new anticancer drug design and development and MM is no exception [86-88]. High throughput virtual screening was used to identify two potent blockers of the ATP binding site of Class I PI3Ks, designated C96 [89] and PIK-C98 [90], that demonstrated good activity against MM in preclinical studies.…”

Section: Non-receptor Serine/threonine Kinase (S/tk) Inhibitorsmentioning

confidence: 99%

Kinase inhibitors as potential agents in the treatment of multiple myeloma

Abramson

2016

Oncotarget

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Recent years have witnessed a dramatic increase in the number of therapeutic options available for the treatment of multiple myeloma (MM) - from immunomodulating agents to proteasome inhibitors to histone deacetylase (HDAC) inhibitors and, most recently, monoclonal antibodies. Used in conjunction with autologous hematopoietic stem cell transplantation, these modalities have nearly doubled the disease's five-year survival rate over the last three decades to about 50%. In spite of these advances, MM still is considered incurable as resistance and relapse are common. While small molecule protein kinase inhibitors have made inroads in the therapy of a number of cancers, to date their application to MM has been less than successful. Focusing on MM, this review examines the roles played by a number of kinases in driving the malignant state and the rationale for target development in the design of a number of kinase inhibitors that have demonstrated anti-myeloma activity in both in vitro and in vivo xenograph models, as well as those that have entered clinical trials. Among the targets and their inhibitors examined are receptor and non-receptor tyrosine kinases, cell cycle control kinases, the PI3K/AKT/mTOR pathway kinases, protein kinase C, mitogen-activated protein kinase, glycogen synthase kinase, casein kinase, integrin-linked kinase, sphingosine kinase, and kinases involved in the unfolded protein response.

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“…[6] However, nowadays more attention has been drawn to the development of PI3K isoform-selective inhibitors because of the successful listing of Idelalisib (CAL-101), the first marketed selective PI3Kδ inhibitor, which was approved by FDA in 2014 for treating chronic lymphocytic leukemia and small lymphocytic lymphoma. [7,8] Recently, Duvelisib (IPI-145), a PI3Kδ/γ dual inhibitor, also has been on the market and that greatly promotes the development of PI3Kγ inhibitors. [9,10] 1 These authors contributed equally to this work.…”

Section: Introductionmentioning

confidence: 99%

Rational Design of Novel Phosphoinositide 3‐Kinase Gamma (PI3Kγ) Selective Inhibitors: A Computational Investigation Integrating 3D‐QSAR, Molecular Docking and Molecular Dynamics Simulation

Zhu

et al. 2019

Chemistry & Biodiversity

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Phosphoinositide 3‐kinase gamma (PI3Kγ) draws an increasing attention due to its link with deadly cancer, chronic inflammation and allergy. But the development of PI3Kγ selective inhibitors is still a challenging endeavor because of the high sequence homology with the other PI3K isoforms. In order to acquire valuable information about the interaction mechanism between potent inhibitors and PI3Kγ, a series of PI3Kγ isoform‐selective inhibitors were analyzed by a systematic computational method, combining 3D‐QSAR, molecular docking, molecular dynamic (MD) simulations, free energy calculations and decomposition. The general structure–activity relationships were revealed and some key residues relating to selectivity and high activity were highlighted. It provides precious guidance for rational virtual screening, modification and design of selective PI3Kγ inhibitors. Finally, ten novel inhibitors were optimized and P10 showed satisfactory predicted bioactivity, demonstrating the feasibility to develop potent PI3Kγ inhibitors through this computational modeling and optimization.

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Discovery of selective phosphatidylinositol 3-kinase inhibitors to treat hematological malignancies

Cited by 47 publications

References 56 publications

Phosphatidylinositol 3‐phosphates—at the interface between cell signalling and membrane traffic

Phosphatidylinositol 3‐phosphates—at the interface between cell signalling and membrane traffic

Kinase inhibitors as potential agents in the treatment of multiple myeloma

Rational Design of Novel Phosphoinositide 3‐Kinase Gamma (PI3Kγ) Selective Inhibitors: A Computational Investigation Integrating 3D‐QSAR, Molecular Docking and Molecular Dynamics Simulation

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