Phosphoinositide 3-kinase inhibitor
A Phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a potential medical drug that functions by inhibiting a Phosphoinositide 3-kinase enzyme which is part of the PI3K/AKT/mTOR pathway, which plays a key role in cancer. Inhibiting this pathway often suppresses tumor growth.[1][2]
There are a number of different classes and isoforms of PI3Ks.[3] Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) - p110 alpha, p110 beta, p110 gamma and p110 delta.[4] The inhibitors being studied inhibit one or more isoforms of the class I PI3Ks.[5][6]
They are being actively investigated for treatment of various cancers.[7][8] [9]
They are also being considered for Inflammatory respiratory disease.[3][5]
Notable examples
- Wortmannin an irreversible inhibitor of PI3K.
- demethoxyviridin a derivative of wortmannin.
- LY294002[5] a reversible inhibitor of PI3K.
Clinical development
Late stage
In phase III clinical trials:
In/starting phase II clinical trials:
Early stage
In early stage clinical trials [9]
- BEZ235[18] The first into clinical trials, in 2006.[19] A PI3K/mTOR dual inhibitor.
- SF1126[20][21][22] Some early clinical data has been presented.[23][24][25] First PI3KI 'Orphan Drug' (for B-cell chronic lymphocytic leukemia (CLL).[26]
- INK1117, a PI3K-alpha inhibitor in phase I.[27]
- IPI-145, a novel inhibitor of PI3K delta and gamma[28],especially for hematologic malignancies (currently in two Phase 1 clinical trials in hematologic cancers as well as a broad range of inflammatory conditions).[29]
- GDC-0941[30][31][32] IC50 of 3nM.
- BKM120[33][34]
- XL147[35][36]
- XL765[37]
- Palomid 529[38]
- GSK615[9]
- ZSTK474,[39] a potent inhibitor against p110a.
- PWT33597, a dual PI3K-alpha/mTOR inhibitor - for advanced solid tumors.[40] IND mid 2011.[41] Phase I recruiting.[42]
Others
- IC87114[5] 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[43]
- PI-103[44] Dual PI3K-mTOR inhibitor.[45]
- SAR245408, SAR245409[46]
- GNE-477 is PI3K-alpha and mTOR inhibitor with IC50 values of 4nM and 21nM.
- CUDC-907, Also an HDAC inhibitor.[47]
See also
References
- ^ [http://www.bioportfolio.com/LeadDiscovery/PubMed-030301.html "PI3K inhibitors: Targeting multiple tumor progression pathways"]. 2003. http://www.bioportfolio.com/LeadDiscovery/PubMed-030301.html.
- ^ Neri, LM; Borgatti, P; Tazzari, PL; Bortul, R; Cappellini, A; Tabellini, G; Bellacosa, A; Capitani, S et al. (2003). "The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells". Molecular cancer research : MCR 1 (3): 234–46. PMID 12556562.
- ^ a b Ito, K; Caramori, G; Adcock, IM (2007). "Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease". The Journal of pharmacology and experimental therapeutics 321 (1): 1–8. doi:10.1124/jpet.106.111674. PMID 17021257.
- ^ Study results provide rationale for use of PI3K inhibitors in therapeutic settings. News-medical.net. Retrieved on 2010-11-05.
- ^ a b c d Crabbe, T (2007). "Exploring the potential of PI3K inhibitors for inflammation and cancer". Biochemical Society transactions 35 (Pt 2): 253–6. doi:10.1042/BST0350253. PMID 17371252.
- ^ Stein, R. (2001). "Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment". Endocrine Related Cancer 8 (3): 237–48. doi:10.1677/erc.0.0080237. PMID 11566615.
- ^ Flanagan (Dec 2008). "Zeroing in on PI3K Pathway". http://www.genengnews.com/articles/chitem.aspx?aid=2695&chid=1.
- ^ Wu, P; Liu, T; Hu, Y (2009). "PI3K inhibitors for cancer therapy: what has been achieved so far?". Current medicinal chemistry 16 (8): 916–30. doi:10.2174/092986709787581905. PMID 19275602.
- ^ a b c Maira, Sauveur-Michel; Stauffer, Frédéric; Schnell, Christian; García-Echeverría, Carlos (2009). "PI3K inhibitors for cancer treatment: where do we stand?". Biochemical Society Transactions 37 (Pt 1): 265–72. doi:10.1042/BST0370265. PMID 19143644.
- ^ Clinicaltrials.gov Search results
- ^ Calistoga Pharmaceuticals presents CAL-101 PI3K inhibitor data at European Hematology Association Congress. News-medical.net. Retrieved on 2010-11-05.
- ^ "Calistoga Pharmaceuticals Announces Initiation of Phase 2 Trial of Delta-Isoform-Selective PI3 Kinase Inhibitor CAL-101 in Combination with Rituximab for the Treatment of Previously Untreated Elderly Patients with Chronic Lymphocytic Leukemia" (Press release). Calistoga Pharmaceuticals. October 19, 2010. http://www.earthtimes.org/articles/press/patients-chronic-lymphocytic-leukemia,1508350.html. Retrieved November 3, 2010.
- ^ Howes, AL; Chiang, GG; Lang, ES; Ho, CB; Powis, G; Vuori, K; Abraham, RT (2007). "The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures". Molecular cancer therapeutics 6 (9): 2505–14. doi:10.1158/1535-7163.MCT-06-0698. PMID 17766839.
- ^ PX-866 June 2010
- ^ ClinicalTrials.gov NCT00726583 Phase I Trial of Oral PX-866
- ^ "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 nov 2010. http://www.medicalnewstoday.com/articles/206625.php.
- ^ http://www.drugrehab.in/2011/01/onty-starts-second-phase-iii-trial-of-pi3k-inhibitor-this-one-is-a-combo-with-merck-kgaas-erbitux/
- ^ Liu, TJ; Koul, D; Lafortune, T; Tiao, N; Shen, RJ; Maira, SM; Garcia-Echevrria, C; Yung, WK (2009). "NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas". Molecular cancer therapeutics 8 (8): 2204–10. doi:10.1158/1535-7163.MCT-09-0160. PMC 2752877. PMID 19671762. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2752877.
- ^ ClinicalTrials.gov NCT00620594 A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer
- ^ Definition of pan-PI3K/mTOR inhibitor SF1126 - National Cancer Institute Drug Dictionary. Cancer.gov. Retrieved on 2010-11-05.
- ^ "Semafore's PI3 Kinase Inhibitor SF1126 Is A Vascular Targeted Conjugate In Phase I Clinical Trials In Solid Tumors And Multiple Myeloma" (Press release). Semafore Pharmaceuticals. April 15, 2008. http://www.medicalnewstoday.com/articles/103948.php. Retrieved November 3, 2010.
- ^ ClinicalTrials.gov NCT00907205 A Dose Escalation Study of SF1126, a PI3 Kinase (PI3K) Inhibitor, Given By Intravenous (IV) Infusion in Patients With Solid Tumors (SF112600106)
- ^ 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
- ^ http://www.globenewswire.com/newsroom/news.html?d=215776
- ^ "Semafore Pharmaceuticals Receives FDA Orphan Drug Designation for SF1126 in the Treatment of Chronic Lymphocytic Leukemia". 9 Nov 2010. http://www.businesswire.com/news/home/20101109005877/en/Semafore-Pharmaceuticals-Receives-FDA-Orphan-Drug-Designation.
- ^ "Intellikine commences INK1117 Phase I dose escalation study in cancer". 12 Oct 2011. http://www.news-medical.net/news/20111012/Intellikine-commences-INK1117-Phase-I-dose-escalation-study-in-cancer.aspx.
- ^ "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". 31 Oct 2011. http://www.finanznachrichten.de/nachrichten-2011-10/21792179-infinity-initiates-two-phase-1-trials-of-ipi-145-a-potent-inhibitor-of-pi3k-delta-and-gamma-004.htm.
- ^ "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". http://www.news-medical.net/news/20111031/Infinity-commences-two-IPI-145-Phase-1-clinical-trials-for-hematologic-malignancies.aspx.
- ^ ClinicalTrials.gov NCT00974584 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
- ^ ClinicalTrials.gov NCT00876109
- ^ ClinicalTrials.gov NCT00876122 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
- ^ ClinicalTrials.gov NCT01068483
- ^ ClinicalTrials.gov NCT01132664
- ^ ClinicalTrials.gov NCT01042925
- ^ "XL147 inc diagram". http://www.kemitek.se/goods.php?id=173.
- ^ ClinicalTrials.gov NCT00485719
- ^ ClinicalTrials.gov NCT01033721
- ^ http://clinicaltrials.gov/ct2/show/NCT01280487 A Safety Study of Oral ZSTK474 in Patients With Cancer
- ^ http://www.genengnews.com/gen-news-highlights/pathway-receives-7-5m-boost-to-take-lead-pi3k-mtor-inhibitor-into-clinical-development/81245208/ 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
- ^ http://www.businesswire.com/news/home/20110815006367/en/Pathway-Therapeutics-Announces-Appointment-Mark-Perry-Dr.
- ^ http://clinicaltrials.gov/ct2/show/NCT01066611 Study to Investigate Effects of CAL-263 in Subjects With Allergic Rhinitis Exposed to Allergen in an Environmental Chamber
- ^ Werzowa et al. (4 Nov 2010). Vertical Inhibition of the mTORC1/mTORC2/PI3K Pathway Shows Synergistic Effects against Melanoma In Vitro and In Vivo. doi:10.1038/jid.2010.327. http://www.nature.com/jid/journal/vaop/ncurrent/full/jid2010327a.html.
- ^ Fan et al.; Cheng, C; Hackett, C; Feldman, M; Houseman, BT; Nicolaides, T; Haas-Kogan, D; James, CD et al. (Nov 2010). "Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma". Science signaling 3 (147): ra81. doi:10.1126/scisignal.2001017. PMC 3001107. PMID 21062993. http://stke.sciencemag.org/cgi/content/abstract/3/147/ra81.
- ^ "Merck and Sanofi-aventis laboratories to collaborate on cancer research". 20 Dec 2010. http://www.labmate-online.com/news/news-and-views/5/breaking_news/merck_and_sanofi-aventis_laboratories_to_collaborate_on_cancer_research/13247/.
- ^ http://www.thestreet.com/story/11312666/1/curis-presents-data-on-pi3k-and-hdac-inhibitor-cudc-907-at-the-2011-aacr-nci-eortc-symposium.html
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