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Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3K? isoform.

ABSTRACT: Development of novel PI3K inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We investigated the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines. The results demonstrated that the PI3K? isoform was identified as a direct target of Brusatol, and inhibition was dramatically reduced on cells with lower PI3K? levels. Novel synthetic analogs were also developed and tested in vitro and in vivo. They shared comparable or superior potency in their ability to inhibit malignant hematologic cell lines, and in a xenograft transplant mouse model. One unique analog had minimal toxicity to normal human cells and in a mouse model. These new analogs have enhanced potential for development as a new class of PI3K inhibitors for treatment of hematologic malignancies.

SUBMITTER: Pei Y

PROVIDER: S-EPMC7253423 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3Kγ isoform.

Pei Yonggang Y Hwang Nicky N Lang Fengchao F Zhou Lanlan L Wong Josiah Hiu-Yuen JH Singh Rajnish Kumar RK Jha Hem Chandra HC El-Deiry Wafik S WS Du Yanming Y Robertson Erle S ES

Communications biology 20200527 1

Development of novel PI3K inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We investigated the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines. The results demonstrated that the PI3Kγ isoform was identified as a direct target of Br ...[more]

PMID: 32461675

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Project description:The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.

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Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3K? isoform.

Publications

Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3Kγ isoform.

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