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]

They are being actively investigated for treatment of various cancers.[8][9] [10]

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

Notable examples[edit]

Approvals[edit]

  • Idelalisib (PI3K Delta inhibitor) FDA approved July 2014 for leukemia and two types of lymphoma.[11]

Clinical development[edit]

Late stage[edit]

In phase III clinical trials:

In/starting phase II clinical trials:

  • PX-866[14][15][16] In 2010 Starting 4 phase II trials for solid tumours.[17][18]
  • IPI-145, a novel inhibitor of PI3K delta and gamma,[19] especially for hematologic malignancies (currently in two Phase 1 clinical trials in hematologic cancers as well as a broad range of inflammatory conditions).[20] July 2012 the phase I trial was expanded and two phase II trials are planned,[21] OK at 75 mg BID, will try 100 mg BID.[22] Also in phase 2a for asthma.[22]
  • BAY 80-6946, predominantly inhibits PI3Kα,δ isoforms.[23]

Early stage[edit]

In early stage clinical trials [10]

Others

See also[edit]

References[edit]

  1. ^ Kurtz J.E. Ray-Coquard I., 2012. PI3 kinase inhibitors in the clinic: an update. [Review]. Anticancer Research, 32(7), pp.2463-70
  2. ^ [http://www.bioportfolio.com/LeadDiscovery/PubMed-030301.html[dead link] "PI3K inhibitors: Targeting multiple tumor progression pathways"]. 2003. 
  3. ^ Neri, LM; Borgatti, P; Tazzari, PL; Bortul, R; Cappellini, A; Tabellini, G; Bellacosa, A; Capitani, S; Martelli, AM (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. 
  4. ^ 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. 
  5. ^ Study results provide rationale for use of PI3K inhibitors in therapeutic settings. News-medical.net. Retrieved on 2010-11-05.
  6. ^ 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. 
  7. ^ Stein, R. (2001). "Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment". Endocrine Related Cancer (Bioscientifica) 8 (3): 237–48. doi:10.1677/erc.0.0080237. PMID 11566615. 
  8. ^ Flanagan (Dec 2008). "Zeroing in on PI3K Pathway". 
  9. ^ 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. 
  10. ^ a b 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. 
  11. ^ "FDA approves Zydelig for three types of blood cancers". US Food and Drug Administration. July 23, 2014. 
  12. ^ Clinicaltrials.gov Search results
  13. ^ Wu, M.; Akinleye, A.; Zhu, X. (2013). "Novel agents for chronic lymphocytic leukemia". Journal of Hematology & Oncology 6: 36. doi:10.1186/1756-8722-6-36. PMC 3659027. PMID 23680477.  edit
  14. ^ 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. 
  15. ^ PX-866 June 2010
  16. ^ Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
  17. ^ "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 Nov 2010. 
  18. ^ http://www.drugrehab.in/2011/01/onty-starts-second-phase-iii-trial-of-pi3k-inhibitor-this-one-is-a-combo-with-merck-kgaas-erbitux/
  19. ^ "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". 31 Oct 2011. 
  20. ^ "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". Retrieved November 28, 2011. 
  21. ^ "Infinity Regains Worldwide Rights to PI3K, FAAH and Early Discovery Programs". 18 July 2012. 
  22. ^ a b Infinity Reports IPI-145 Phase 1 Data Showing Clinical Activity in B-Cell and T-Cell Malignancies at ASH Annual Meeting. Dec 2012
  23. ^ Bayer to Present New Data on Growing Oncology Pipeline. April 2013
  24. ^ 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. 
  25. ^ 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
  26. ^ Serra, V; Markman, B; Scaltriti, M; Eichhorn, PJA; Valero, V; Guzman, M; Botero, ML; Llonch, E; Atzori, F.; Di Cosimo, S.; Maira, M.; Garcia-Echeverria, C.; Parra, J. L.; Arribas, J.; Baselga, J. (2008). "NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations". Cancer Research 68 (19): 8022–30. doi:10.1158/0008-5472.CAN-08-1385. PMID 18829560. 
  27. ^ http://globenewswire.com/news-release/2013/12/06/595118/10060659/en/Rhizen-Pharmaceuticals-S-A-announces-initiation-of-a-First-in-Human-Phase-1-trial-of-RP6530-a-dual-PI3K-delta-gamma-inhibitor-in-patients-with-hematological-malignancies.html
  28. ^ http://clinicaltrials.gov/ct2/show/NCT01767766?term=tgr1202&rank=1
  29. ^ Definition of pan-PI3K/mTOR inhibitor SF1126 - National Cancer Institute Drug Dictionary. Cancer.gov. Retrieved on 2010-11-05.
  30. ^ "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. Retrieved November 3, 2010. 
  31. ^ 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
  32. ^ Semafore's SF1126 peptidic prodrug demonstrates clinical activity in chronic lymphocytic leukemia. News-medical.net. Retrieved on 2010-11-05.
  33. ^ Update on the Novel Prodrug Dual mTOR‐PI3K Inhibitor SF1126
  34. ^ http://www.globenewswire.com/newsroom/news.html?d=215776
  35. ^ "Semafore Pharmaceuticals Receives FDA Orphan Drug Designation for SF1126 in the Treatment of Chronic Lymphocytic Leukemia". 9 Nov 2010. 
  36. ^ "Intellikine commences INK1117 Phase I dose escalation study in cancer". 12 Oct 2011. 
  37. ^ 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
  38. ^ Clinical trial number NCT00876109 at ClinicalTrials.gov
  39. ^ 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
  40. ^ Clinical trial number NCT01068483 at ClinicalTrials.gov
  41. ^ Clinical trial number NCT01132664 at ClinicalTrials.gov
  42. ^ Clinical trial number NCT01042925 at ClinicalTrials.gov
  43. ^ Clinical trial number NCT00485719 at ClinicalTrials.gov
  44. ^ Clinical trial number NCT01033721 at ClinicalTrials.gov
  45. ^ "GSK Clinical Register: PIK111051". 
  46. ^ http://clinicaltrials.gov/ct2/show/NCT01280487 A Safety Study of Oral ZSTK474 in Patients With Cancer
  47. ^ 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
  48. ^ 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
  49. ^ http://www.businesswire.com/news/home/20110815006367/en/Pathway-Therapeutics-Announces-Appointment-Mark-Perry-Dr.
  50. ^ 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
  51. ^ http://rhizen.com/News%20&%20PR/Rhizen_Press%20Release_ATS_May'13.pdf
  52. ^ http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2013.187.1_MeetingAbstracts.A3880
  53. ^ Werzowa et al. (4 Nov 2010). "Vertical Inhibition of the mTORC1/mTORC2/PI3K Pathway Shows Synergistic Effects against Melanoma In Vitro and In Vivo". Journal of Investigative Dermatology 131 (2): 495–503. doi:10.1038/jid.2010.327. PMID 21048785. 
  54. ^ Fan 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.  |first10= missing |last10= in Authors list (help); |first11= missing |last11= in Authors list (help); |first12= missing |last12= in Authors list (help)
  55. ^ 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
  56. ^ http://www.nasdaq.com/article/curis-achieves-cudc-907-milestones-under-its-agreement-with-the-leukemia--lymphoma-society-20121018-00214
  57. ^ 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

Further reading[edit]

  • 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[edit]