Phosphoinositide 3-kinase inhibitor

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Overview of phosphoinositide 3-kinase (PI3K) inhibitors and their interaction with the PI3K/AKT/mTOR pathway. There are pan-class I PI3K inhibitors such as copanlisib, isoform-specific PI3K inhibitors such as idelalisib, and dual PI3K/mTOR inhibitors such as dactolisib. Note that fimepinostat and rigosertib inhibit the PI3K/AKT/mTOR pathway, but not PI3K itself. PI3K inhibitors overview Mishra2021.jpg
Overview of phosphoinositide 3-kinase (PI3K) inhibitors and their interaction with the PI3K/AKT/mTOR pathway. There are pan-class I PI3K inhibitors such as copanlisib, isoform-specific PI3K inhibitors such as idelalisib, and dual PI3K/mTOR inhibitors such as dactolisib. Note that fimepinostat and rigosertib inhibit the PI3K/AKT/mTOR pathway, but not PI3K itself.

Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. [2] [3] They are examples of a targeted therapy. [4] While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable. [5] [6]

Contents

After PI3K inhibitors had been under investigation as anti-cancer drugs for several years, [7] [8] [9] [10] the first one to be approved for treatment in clinical practice was idelalisib in 2014. [11] Several others followed, and even more are still under development (see below). [3] [12]

There are different classes and isoforms of PI3Ks. [13] Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha (PIK3CA), p110 beta (PIK3CB), p110 gamma (PIK3CG) and p110 delta (PIK3CD). [14] All PI3K inhibitors that are currently approved inhibit one or more p110 isoforms of the class I PI3Ks. Inhibiting different p110 isoforms can have different effects, [15] e.g. PTEN-negative tumors may be more sensitive to PIK3CB inhibitors. [15]

PI3K inhibitors are also under investigation as treatments for inflammatory respiratory disease, [13] [16] and are used to investigate the role of the PI3K pathway in aging. [17]

Approved for treatment

Under clinical development

Late stage

In phase III clinical trials:

In phase II clinical trials:

Early stage

In early stage clinical trials [9]

Not in clinical trials

See also

Related Research Articles

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Bruton's tyrosine kinase, also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.

<span class="mw-page-title-main">PI3K/AKT/mTOR pathway</span> Cell cycle regulation pathway

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and CaM. Both leptin and insulin recruit PI3K signalling for metabolic regulation. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9.

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Tower Cancer Research Foundation (TCRF) is a 501(c)(3) non-profit organization dedicated to clinical research, patient support and community education. It was established in 1996 in Beverly Hills, California.

<span class="mw-page-title-main">Dactolisib</span> Chemical compound

Dactolisib is an imidazoquinoline derivative acting as a PI3K inhibitor. It also inhibits mTOR. It is being investigated as a possible cancer treatment.

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

<span class="mw-page-title-main">Abexinostat</span> Chemical compound

Abexinostat is an experimental drug candidate for cancer treatment. It was developed by Pharmacyclics and licensed to Xynomic. As of 2013, it was in Phase II clinical trials for B-cell lymphoma. Pre-clinical study suggests the potential for treatment of different types of cancer as well.

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<span class="mw-page-title-main">Idelalisib</span> Chemical compound

Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers. Idelalisib acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase. It was developed by Gilead Sciences. It is taken orally.

<span class="mw-page-title-main">Copanlisib</span> Chemical compound

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<span class="mw-page-title-main">Buparlisib</span> Chemical compound

Buparlisib is an experimental anti-cancer medication. It is a small molecule orally-available pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. Buparlisib was under investigation as a treatment for advanced breast cancer but was abandoned due to negative results. It is still under investigation as a potential treatment for head and neck squamous cell carcinoma (HNSCC).

<span class="mw-page-title-main">Duvelisib</span> PI3K inhibitor

Duvelisib, sold under the brand name Copiktra, is a medication used to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma after other treatments have failed. It is taken by mouth. It is a PI3 kinase inhibitor.

<span class="mw-page-title-main">Abemaciclib</span> Anti-breast cancer medication

Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.

<span class="mw-page-title-main">Umbralisib</span> Chemical compound

Umbralisib, sold under the brand name Ukoniq, is an anti-cancer medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). It is taken by mouth.

<span class="mw-page-title-main">Gedatolisib</span> Chemical compound

Gedatolisib (PF-05212384) is an experimental drug for treatment of cancer in development by Celcuity, Inc. The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.

Verastem, Inc., doing business as Verastem Oncology, is an American pharmaceutical company that develops medicines to treat certain cancers. Headquartered and founded in Boston, Massachusetts, the firm is a member of NASDAQ Biotechnology Index.

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Indolent lymphoma, also known as low-grade lymphoma, is a group of slow-growing non-Hodgkin lymphomas (NHLs). Because they spread slowly, they tend to have fewer signs and symptoms when first diagnosed and may not require immediate treatment. Symptoms can include swollen but painless lymph nodes, unexplained fever, and unintended weight loss.

<span class="mw-page-title-main">Inavolisib</span> Chemical compound

Inavolisib, or GDC-0077, is an investigational, highly selective inhibitor and degrader of mutant phosphatidylinositol 3-kinase (PI3K) alpha. The PI3K-mediated signalling pathway has shown to play an important role in the development of tumours as dysregulation is commonly associated with tumour growth and resistance to antineoplastic agents and radiotherapy.

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Further reading