Phosphoinositide 3-kinase inhibitor
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A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is 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] SF1126 is the first PI-3 kinase inhibitor to enter pediatric cancer clinical trials via the NANT consortium.
They are being actively investigated for treatment of various cancers.[8][9] [10]
They are also being considered for inflammatory respiratory disease.[4][6]
Contents
Notable examples
- Wortmannin an irreversible inhibitor of PI3K.
- demethoxyviridin a derivative of wortmannin.
- LY294002[6] a reversible inhibitor of PI3K.
Approvals
- Idelalisib (PI3K Delta inhibitor) FDA approved July 2014 for leukemia and two types of lymphoma.[11]
Clinical development
Late stage
- Perifosine, for colorectal cancer and multiple myeloma. (discontinued 2013)
- Idelalisib[12] an oral PI3K delta inhibitor for chronic lymphocytic leukaemia.[13]
- BKM120[14][15] (buparlisib) for HR+/HER2 advanced endocrine-resistant breast cancer.[16]
- Duvelisib, (IPI-145) a novel inhibitor of PI3K delta and gamma,[17] especially for hematologic malignancies and inflammatory conditions.[18] It is in 4 active phase 3 trials.
In/starting phase II clinical trials:
- PX-866[19][20][21] In 2010 Starting 4 phase II trials for solid tumours.[22][23]
- BAY 80-6946, predominantly inhibits PI3Kα,δ isoforms.[24]
Early stage
In early stage clinical trials [10]
- BEZ235[25] The first into clinical trials, in 2006.[26] A PI3K/mTOR dual inhibitor.[27]
- RP6530, Dual PI3K delta/gamma inhibitor for lymphomas.[28]
- TGR 1202, oral PI3K delta inhibitor (previously known as RP5264). Phase I recruiting [29]
- SF1126[30][31][32] Some early clinical data has been presented.[33][34][35] First PI3KI 'Orphan Drug' for B-cell chronic lymphocytic leukemia (CLL).[36]
- INK1117, a PI3K-alpha inhibitor in phase I.[37]
- GDC-0941[38][39][40] IC50 of 3nM.
- XL147 (also known as SAR245408)[41]
- XL765 (also known as SAR245409)[42]
- Palomid 529[43]
- GSK1059615 The phase I trial of this drug was terminated due to lack of sufficient exposure following single- and repeat- dosing.[44]
- ZSTK474,[45] a potent inhibitor against p110a.
- PWT33597, a dual PI3K-alpha/mTOR inhibitor - for advanced solid tumors.[46] IND mid 2011.[47] Phase I recruiting.[48]
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[49]
- RP6503,Dual PI3K delta/gamma inhibitor for the treatment of Asthma and COPD (Late pre-clinical stage).[50][51]
- PI-103[52] Dual PI3K-mTOR inhibitor.[53]
- GNE-477 is PI3K-alpha and mTOR inhibitor with IC50 values of 4nM and 21nM.
- CUDC-907, Also an HDAC inhibitor.[54] IND has been filed.[55]
- AEZS-136, also inhibits Erk1/2.[56]
See also
- PI3K/AKT/mTOR pathway for inhibitors of AKT and mTOR downstream from PI3K
References
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External links
- ↑ Kurtz J.E. Ray-Coquard I., 2012. PI3 kinase inhibitors in the clinic: an update. [Review]. Anticancer Research, 32(7), pp.2463-70
- ↑ Lua error in package.lua at line 80: module 'strict' not found.[dead link]
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Study results provide rationale for use of PI3K inhibitors in therapeutic settings. News-medical.net. Retrieved on 2010-11-05.
- ↑ 6.0 6.1 6.2 6.3 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
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- ↑ 10.0 10.1 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Clinical trial number NCT01068483 at ClinicalTrials.gov
- ↑ Clinical trial number NCT01132664 at ClinicalTrials.gov
- ↑ PI3K Inhibitor Penetrates Endocrine-Resistant Breast Cancer. Dec 2015
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ PX-866 June 2010
- ↑ Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ http://www.drugrehab.in/2011/01/onty-starts-second-phase-iii-trial-of-pi3k-inhibitor-this-one-is-a-combo-with-merck-kgaas-erbitux/
- ↑ Bayer to Present New Data on Growing Oncology Pipeline. April 2013
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Clinical trial number NCT00620594 for "A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer" at ClinicalTrials.gov
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Definition of pan-PI3K/mTOR inhibitor SF1126 - National Cancer Institute Drug Dictionary. Cancer.gov. Retrieved on 2010-11-05.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Clinical trial number NCT00907205 for "A Dose Escalation Study of SF1126, a PI3 Kinase (PI3K) Inhibitor, Given By Intravenous (IV) Infusion in Patients With Solid Tumors (SF112600106)" at ClinicalTrials.gov
- ↑ Semafore's SF1126 peptidic prodrug demonstrates clinical activity in chronic lymphocytic leukemia. News-medical.net. Retrieved on 2010-11-05.
- ↑ Update on the Novel Prodrug Dual mTOR‐PI3K Inhibitor SF1126
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Clinical trial number NCT00974584 for "A Study of the Safety and Pharmacology of PI3-Kinase Inhibitor GDC-0941 in Combination With Paclitaxel and Carboplatin With or Without Bevacizumab in Patients With Advanced Non-Small Cell Lung Cancer" at ClinicalTrials.gov
- ↑ Clinical trial number NCT00876109 at ClinicalTrials.gov
- ↑ Clinical trial number NCT00876122 for "A Study of GDC-0941 in Patients With Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma for Which Standard Therapy Either Does Not Exist or Has Proven Ineffective or Intolerable" at ClinicalTrials.gov
- ↑ Clinical trial number NCT01042925 at ClinicalTrials.gov
- ↑ Clinical trial number NCT00485719 at ClinicalTrials.gov
- ↑ Clinical trial number NCT01033721 at ClinicalTrials.gov
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ A Safety Study of Oral ZSTK474 in Patients With Cancer
- ↑ Pathway Receives $7.5M Boost to Take Lead PI3K/mTOR Inhibitor into Clinical Development. 25 May 2011
- ↑ http://gamutnews.com/20110525/8934/fda-approves-trial-of-pathway-therapeutics-inc-cancer-drug-7-5-million-financing-in-place-to-advance-novel-pi3kmtor-inhibitor-portfolio.html
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Study to Investigate Effects of CAL-263 in Subjects With Allergic Rhinitis Exposed to Allergen in an Environmental Chamber
- ↑ http://rhizen.com/News%20&%20PR/Rhizen_Press%20Release_ATS_May'13.pdf
- ↑ http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2013.187.1_MeetingAbstracts.A3880
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
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- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ http://www.marketwatch.com/story/aeterna-zentaris-presents-preclinical-data-for-its-anti-cancer-pi3k-erk-12-inhibitor-aezs-136-at-aacr-meeting-2012-04-03-73000
