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. These anti-cancer drugs are examples of targeted therapy.
There are a number of different classes and isoforms of PI3Ks. Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) - p110 alpha, p110 beta, p110 gamma and p110 delta. The inhibitors being studied inhibit one or more isoforms of the class I PI3Ks.
They are being actively investigated for treatment of various cancers.
They are also being considered for inflammatory respiratory disease.
Video Phosphoinositide 3-kinase inhibitor
Effects of inhibiting different isoforms
Inhibiting different p110 isoforms can have different effects. e.g. PTEN-negative tumors may be more sensitive to p110? inhibitors.
Maps Phosphoinositide 3-kinase inhibitor
Notable examples
- Wortmannin an irreversible inhibitor of PI3K.
- demethoxyviridin a derivative of wortmannin.
- LY294002 a reversible inhibitor of PI3K.
Approvals
- Idelalisib (PI3K Delta inhibitor) FDA approved July 2014 for leukemia and two types of lymphoma.
- Copanlisib (Inhibitor of phosphatidylinositol-3-kinase, predominantly against PI3K-? and PI3K-?) 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.
Clinical development
Late stage
In phase III clinical trials:
- Taselisib, an investigational PI3K inhibitor, is currently in clinical development based on its potential selectivity for the PI3K? isoform.1,2 Preclinical data have shown that taselisib induced growth inhibition in PI3K?-mutant cell lines.1 Taselisib continues to be investigated in ongoing clinical studies. This is being developed by Roche Genentech.
- Perifosine, for colorectal cancer and multiple myeloma. (discontinued 2013)
- Idelalisib also for chronic lymphocytic leukaemia. Trials for CLL terminated/abandoned in 2015.
- Idelalisib for follicular lymphoma. A dose optimization study
- Buparlisib (BKM120) for HR+/HER2 advanced endocrine-resistant breast cancer - encouraging results in Dec 2015.
- Duvelisib, (IPI-145) a novel inhibitor of PI3K delta and gamma, especially for hematologic malignancies and inflammatory conditions. It has started 4 phase 3 trials but in Nov 2016 Infinity exclusively licensed it to Verastem.
- Alpelisib (BYL719), an alpha-specific PI3K inhibitor, starting SOLAR-1 trial for PIK3CA-altered metastatic breast cancer. Trial to end July 2019.
- Umbralisib, (TGR 1202), oral PI3K delta inhibitor (previously known as RP5264). "has shown promising efficacy with a superior toxicity profile compared with idelalisib" Now in ph3 for CLL. 3 year data (inc Follicular Lymphoma and DLBCL) announced June 2016. Once daily administration. Named Umbralisib, and in combination trials for various lymphomas.
- Copanlisib (BAY 80-6946), predominantly inhibits PI3K?,? isoforms. for indolent non-Hodgkin lymphoma.
In/starting phase II clinical trials:
- PX-866 In 2010 Starting 4 phase II trials for solid tumours. Mixed results since 2012.
- Dactolisib The first into clinical trials, in 2006. A PI3K/mTOR dual inhibitor.
- CUDC-907, Also an HDAC inhibitor. In phase 2 clinical trial for advanced thyroid cancer.
Early stage
With phase I results announced :
- CUDC-907, Also an HDAC inhibitor. In 2016 it was reported as showing promising preliminary evidence of response in patients with diffuse large B-cell lymphoma. In phase 2 clinical trial for advanced thyroid cancer.
- ME-401, PI3K-Delta Inhibitor.
- IPI-549, a PI3K-gamma inhibitor, in phase 1 for various cancers. Phase I results announced Sept 2016.
- SF1126 Some early clinical data has been presented. First PI3KI 'Orphan Drug' for B-cell chronic lymphocytic leukemia (CLL). SF1126 is the first PI-3 kinase inhibitor to enter pediatric cancer clinical trials via the NANT consortium.
In early stage clinical trials
- RP6530, Dual PI3K delta/gamma inhibitor for lymphomas.
- INK1117, a PI3K-alpha inhibitor in phase I.
- pictilisib (GDC-0941) IC50 of 3nM.
- XL147 (also known as SAR245408)
- XL765 (also known as SAR245409)
- Palomid 529
- GSK1059615 The phase I trial of this drug was terminated due to lack of sufficient exposure following single- and repeat- dosing.
- ZSTK474, a potent inhibitor against p110a.
- PWT33597, a dual PI3K-alpha/mTOR inhibitor - for advanced solid tumors. IND mid 2011. Phase I recruiting.
Others
- IC87114 a selective inhibitor of p110?. It has an IC50 of 100 nM for inhibition of p110-?.
- TG100-115, inhibits all four isoforms but has a 5-10 fold better potency against p110-? and p110-?.
- CAL263
- RP6503, Dual PI3K delta/gamma inhibitor for the treatment of Asthma and COPD (Late pre-clinical stage).
- PI-103 Dual PI3K-mTOR inhibitor.
- GNE-477 is PI3K-alpha and mTOR inhibitor with IC50 values of 4nM and 21nM.
- AEZS-136, also inhibits Erk1/2.
See also
- PI3K/AKT/mTOR pathway for inhibitors of AKT and mTOR downstream from PI3K
- P110?#Pharmacology, P110? (PI3K-delta) as a drug target
References
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.
External links
- Novartis on BEZ235 and BKM120 PI3K inhibitors
Source of article : Wikipedia
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