Phosphoinositide 3-kinase inhibitor

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.

Approvals
  • 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]

Clinical development

Late stage

In phase III clinical trials:

  • Taselisib, has potential selectivity for the PI3Kα isoform.1,2. In trials for breast cancer and lung cancer.
  • Perifosine, for colorectal cancer and multiple myeloma. (discontinued 2013)
  • Idelalisib[18] also for chronic lymphocytic leukaemia.[19] Phase 3 drug combination Trials in first-line CLL and second-line NHL were terminated in 2016 due to increased toxicity and mortality.[20]
  • Idelalisib for follicular lymphoma. A dose optimization study[21]
  • Buparlisib (BKM120)[22][23] for HR+/HER2 advanced endocrine-resistant breast cancer – encouraging results in Dec 2015.[24]
  • Duvelisib, (IPI-145) a novel inhibitor of PI3K delta and gamma,[25] especially for hematologic malignancies and inflammatory conditions.[26] It has started 4 phase 3 trials but in Nov 2016 Infinity exclusively licensed it to Verastem.
  • Umbralisib, (TGR 1202), oral PI3K delta inhibitor (previously known as RP5264).[27] "has shown promising efficacy with a superior toxicity profile compared with idelalisib"[28] Now in ph3 for CLL.[29] 3 year data (inc Follicular Lymphoma and DLBCL) announced June 2016.[30] Once daily administration. Named Umbralisib, and in combination trials for various lymphomas.[31]
  • Copanlisib (BAY 80-6946), predominantly inhibits PI3Kα,δ isoforms.[32] for indolent non-Hodgkin lymphoma.[28]

In/starting phase II clinical trials:

Early stage

With phase I results announced :

In early stage clinical trials[10]

  • RP6530, Dual PI3K delta/gamma inhibitor for lymphomas.[56]
  • INK1117, a PI3K-alpha inhibitor in phase I.[57]
  • pictilisib[58] (GDC-0941)[59][60][61] IC50 of 3nM.
  • XL147 (also known as SAR245408)[62]
  • Palomid 529[63]
  • GSK1059615 The phase I trial of this drug was terminated due to lack of sufficient exposure following single- and repeat- dosing.[64]
  • ZSTK474,[65] a potent inhibitor against p110a.
  • PWT33597, a dual PI3K-alpha/mTOR inhibitor – for advanced solid tumors.[66] IND mid 2011.[67] Phase I recruiting.[68]

Others

  • IC87114[6] a selective inhibitor of p110δ. It has an IC50 of 100 nM for inhibition of p110-δ.
  • TG100–115, inhibits all four isoforms but has a 5–10 fold better potency against p110-γ and p110-δ.
  • CAL263[69]
  • RP6503, Dual PI3K delta/gamma inhibitor for the treatment of Asthma and COPD (Late pre-clinical stage).[70][71]
  • PI-103[72] Dual PI3K-mTOR inhibitor.[73]
  • GNE-477 is PI3K-alpha and mTOR inhibitor with IC50 values of 4nM and 21nM.
  • AEZS-136, also inhibits Erk1/2.[74]

See also
  • PI3K/AKT/mTOR pathway for inhibitors of AKT and mTOR downstream from PI3K
  • P110δ#Pharmacology, P110δ (PI3K-delta) as a drug target

References
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Further reading
  • Williams, Roger; Berndt, Alex; Miller, Simon; Hon, Wai-Ching; Zhang, Xuxiao (2009). "Form and flexibility in phosphoinositide 3-kinases". Biochemical Society Transactions. 37 (Pt 4): 615–626. doi:10.1042/BST0370615. PMID 19614567.
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