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

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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.

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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.

References

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  75. ↑ Clinical trial number NCT02724020 for "MLN0128 and MLN0128 + MLN1117 Compared With Everolimus in the Treatment of Adults With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma" at ClinicalTrials.gov
  76. ↑ Clinical trial number NCT02725268 for "A Study of Sapanisertib, Combination of Sapanisertib With MLN1117, Paclitaxel and Combination of Sapanisertib With Paclitaxel in Women With Endometrial Cancer" at ClinicalTrials.gov
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  80. ↑ Clinical trial number NCT03711578 for "Efficacy and Safety Study of Tenalisib (RP6530), a Novel PI3K δ/γ Dual Inhibitor in Patients With Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma (iNHL)" at ClinicalTrials.gov
  81. ↑ "In Focus: Voxtalisib for CLL and B-Cell Lymphomas". Cancer Therapy Advisor. March 27, 2018.
  82. ↑ Clinical trial number NCT01403636 for "A Study of Investigational SAR245409 in Patients With Certain Lymphoma or Leukemia" at ClinicalTrials.gov
  83. ↑ Clinical trial number NCT02540928 for "AMG 319 in HPV Positive and Negative HNSCC" at ClinicalTrials.gov
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