Phosphoinositide 3-kinase inhibitor explained

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.[1] [2] They are examples of a targeted therapy.[3] 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.[4] [5]

After PI3K inhibitors had been under investigation as anti-cancer drugs for several years,[6] [7] [8] [9] the first one to be approved for treatment in clinical practice was idelalisib in 2014.[10] Several others followed, and even more are still under development (see below).[2] [11]

There are different classes and isoforms of PI3Ks. 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).[12] 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,[13] e.g. PTEN-negative tumors may be more sensitive to PIK3CB inhibitors.[13]

PI3K inhibitors are also under investigation as treatments for inflammatory respiratory disease,[14] [15] and are used to investigate the role of the PI3K pathway in aging.[16]

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[8]

Not in clinical trials

See also

Further reading

External links

Notes and References

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  2. Sabbah DA, Hajjo R, Bardaweel SK, Zhong HA . Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020) . Expert Opinion on Therapeutic Patents . 31 . 10 . 877–892 . October 2021 . 33970742 . 10.1080/13543776.2021.1924150 . 234360275 .
  3. 10.1038/s41392-021-00572-w. Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives . 2021 . Zhong . Lei . Li . Yueshan . Xiong . Liang . Wang . Wenjing . Wu . Ming . Yuan . Ting . Yang . Wei . Tian . Chenyu . Miao . Zhuang . Wang . Tianqi . Yang . Shengyong . Signal Transduction and Targeted Therapy . 6 . 1 . 201 . 34054126 . 8165101 .
  4. Curigliano G, Shah RR . Safety and Tolerability of Phosphatidylinositol-3-Kinase (PI3K) Inhibitors in Oncology . Drug Safety . 42 . 2 . 247–262 . February 2019 . 30649751 . 10.1007/s40264-018-0778-4 . 58657824 .
  5. Hanlon A, Brander DM . Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors . Hematology. American Society of Hematology. Education Program . 2020 . 1 . 346–356 . December 2020 . 33275709 . 7727518 . 10.1182/hematology.2020000119 .
  6. Web site: Zeroing in on PI3K Pathway . https://archive.today/20130124041737/http://www.genengnews.com/articles/chitem.aspx?aid=2695&chid=1 . dead . 2013-01-24 . Dec 2008 . Flanagan.
  7. Wu P, Liu T, Hu Y . PI3K inhibitors for cancer therapy: what has been achieved so far? . Current Medicinal Chemistry . 16 . 8 . 916–930 . 2009 . 19275602 . 10.2174/092986709787581905 .
  8. Maira SM, Stauffer F, Schnell C, García-Echeverría C . PI3K inhibitors for cancer treatment: where do we stand? . Biochemical Society Transactions . 37 . Pt 1 . 265–272 . February 2009 . 19143644 . 10.1042/BST0370265 .
  9. Heavey S, O'Byrne KJ, Gately K . Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC . Cancer Treatment Reviews . 40 . 3 . 445–456 . April 2014 . 24055012 . 10.1016/j.ctrv.2013.08.006 .
  10. Web site: FDA approves Zydelig for three types of blood cancers . July 23, 2014 . US Food and Drug Administration.
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  12. http://www.news-medical.net/news/20100810/Study-results-provide-rationale-for-use-of-PI3K-inhibitors-in-therapeutic-settings.aspx Study results provide rationale for use of PI3K inhibitors in therapeutic settings
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  15. Crabbe T . Exploring the potential of PI3K inhibitors for inflammation and cancer . Biochemical Society Transactions . 35 . Pt 2 . 253–256 . April 2007 . 17371252 . 10.1042/BST0350253 .
  16. Blagosklonny MV. Anti-aging: senolytics or gerostatics (unconventional view). Oncotarget. 2021 Aug 31;12(18):1821-1835.
  17. Web site: FDA approves new treatment for adults with relapsed follicular lymphoma . September 14, 2017 . US Food and Drug Administration.
  18. Web site: FDA Approval for duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) . September 24, 2018 . US Food and Drug Administration.
  19. Web site: FDA approves first PI3K inhibitor for breast cancer. Food and Drug Administration. 2019-05-24.
  20. Web site: Ukoniq (umbralisib) tablets, for oral use . TG Therapeutics .
  21. Web site: FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma . U.S. Food and Drug Administration (FDA) . 5 February 2021 . 5 February 2021.
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  32. Zydelig : EPAR - Scientific conclusions. 2016-11-21.
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