Phosphoinositide 3-kinase inhibitor

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A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a class of medical drug that functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signalling pathway for many cellular functions such as growth control, metabolism and translation initiation. Within this pathway there are many components, inhibition of which may result in tumor suppression.[1] These anti-cancer drugs are examples of targeted therapy.[2][3]

There are a number of different classes and isoforms of PI3Ks.[4] Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha, p110 beta, p110 gamma and p110 delta.[5] The inhibitors being studied inhibit one or more isoforms of the class I PI3Ks.[6][7]

They are being actively investigated for treatment of various cancers,[8][9] [10] both alone and in combination.[11]

They are also being considered for inflammatory respiratory disease.[4][6]

Effects of inhibiting different isoforms

Inhibiting different p110 isoforms can have different effects.[12] e.g. PTEN-negative tumors may be more sensitive to p110β inhibitors.[12]

Notable examples

  • Wortmannin: an irreversible inhibitor of PI3K.
  • LY294002:[6] a reversible inhibitor of PI3K.
  • hibiscone C: an irreversible inhibitor of PI3K.


  • Idelalisib (PI3K Delta inhibitor) FDA approved July 2014 for relapsed or refractory chronic lymphocytic leukemia (CLL) in combination with rituximab, relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies, and 3rd line follicular lymphoma in patients who have received at least two prior systemic therapies.[13]
  • Copanlisib (Inhibitor of PI3K, predominantly against PI3K-α and PI3K-δ) FDA approved in September 2017 for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.[14]
  • Duvelisib (an oral dual inhibitor of PI3K-delta and PI3K-gamma) FDA approved duvelisib on September 24, 2018. Duvelisib is approved for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies, and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies.[15]
  • Alpelisib (BYL719), an alpha-specific PI3K inhibitor,[16] approved by the FDA in May 2019 for use in combination with endocrine therapy fulvestrant for treatment of HR-positive and HER2/neu-negative breast cancer.[17]
  • Umbralisib was approved for medical use in the United States in February 2021.[18][19] Umbralisib is indicated for adults with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen; and adults with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.[18][20]

Clinical development

Late stage

In phase III clinical trials:

In/starting phase II clinical trials:

Early stage

With phase I results announced :

In early stage clinical trials[10]


See also


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Further reading

  • Williams R, Berndt A, Miller S, Hon WC, Zhang X (August 2009). "Form and flexibility in phosphoinositide 3-kinases". Biochemical Society Transactions. 37 (Pt 4): 615–26. doi:10.1042/BST0370615. PMID 19614567.

External links