Phosphoinositide 3-kinase inhibitor

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The PI3K/AKT/mTOR pathway is an important signalling pathway for many cellular functions such as growth control, metabolism and translation initiation. Within this pathway there are many valuable anti-cancer drug treatment targets and for this reason it has been subject to a lot of research in recent years.[1] 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 this pathway and therefore, through inhibition, often results in tumour suppression.[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]

Clinical development[edit]

Late stage[edit]

In phase III clinical trials:

In/starting phase II clinical trials:

  • PX-866[13][14][15] In 2010 Starting 4 phase II trials for solid tumours.[16][17]
  • IPI-145, a novel inhibitor of PI3K delta and gamma,[18] especially for hematologic malignancies (currently in two Phase 1 clinical trials in hematologic cancers as well as a broad range of inflammatory conditions).[19] July 2012 the phase I trial was expanded and two phase II trials are planned,[20] OK at 75 mg BID, will try 100 mg BID.[21] Also in phase 2a for asthma.[21]
  • BAY 80-6946, predominantly inhibits PI3Kα,δ isoforms.[22]

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 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. ^ Clinicaltrials.gov Search results
  12. ^ 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
  13. ^ 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. 
  14. ^ PX-866 June 2010
  15. ^ ClinicalTrials.gov NCT00726583 Phase I Trial of Oral PX-866
  16. ^ "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 Nov 2010. 
  17. ^ http://www.drugrehab.in/2011/01/onty-starts-second-phase-iii-trial-of-pi3k-inhibitor-this-one-is-a-combo-with-merck-kgaas-erbitux/
  18. ^ "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". 31 Oct 2011. 
  19. ^ "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". Retrieved November 28, 2011. 
  20. ^ "Infinity Regains Worldwide Rights to PI3K, FAAH and Early Discovery Programs". 18 July 2012. 
  21. ^ 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
  22. ^ Bayer to Present New Data on Growing Oncology Pipeline. April 2013
  23. ^ 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. 
  24. ^ ClinicalTrials.gov NCT00620594 A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer
  25. ^ 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. 
  26. ^ 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
  27. ^ http://clinicaltrials.gov/ct2/show/NCT01767766?term=tgr1202&rank=1
  28. ^ Definition of pan-PI3K/mTOR inhibitor SF1126 - National Cancer Institute Drug Dictionary. Cancer.gov. Retrieved on 2010-11-05.
  29. ^ "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. 
  30. ^ 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)
  31. ^ Semafore's SF1126 peptidic prodrug demonstrates clinical activity in chronic lymphocytic leukemia. News-medical.net. Retrieved on 2010-11-05.
  32. ^ Update on the Novel Prodrug Dual mTOR‐PI3K Inhibitor SF1126
  33. ^ http://www.globenewswire.com/newsroom/news.html?d=215776
  34. ^ "Semafore Pharmaceuticals Receives FDA Orphan Drug Designation for SF1126 in the Treatment of Chronic Lymphocytic Leukemia". 9 Nov 2010. 
  35. ^ "Intellikine commences INK1117 Phase I dose escalation study in cancer". 12 Oct 2011. 
  36. ^ 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
  37. ^ ClinicalTrials.gov NCT00876109
  38. ^ 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
  39. ^ ClinicalTrials.gov NCT01068483
  40. ^ ClinicalTrials.gov NCT01132664
  41. ^ ClinicalTrials.gov NCT01042925
  42. ^ ClinicalTrials.gov NCT00485719
  43. ^ ClinicalTrials.gov NCT01033721
  44. ^ "GSK Clinical Register: PIK111051". 
  45. ^ http://clinicaltrials.gov/ct2/show/NCT01280487 A Safety Study of Oral ZSTK474 in Patients With Cancer
  46. ^ 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
  47. ^ 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
  48. ^ http://www.businesswire.com/news/home/20110815006367/en/Pathway-Therapeutics-Announces-Appointment-Mark-Perry-Dr.
  49. ^ 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
  50. ^ http://rhizen.com/News%20&%20PR/Rhizen_Press%20Release_ATS_May'13.pdf
  51. ^ http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2013.187.1_MeetingAbstracts.A3880
  52. ^ Werzowa et al.; Koehrer, Stefan; Strommer, Sabine; Cejka, Daniel; Fuereder, Thorsten; Zebedin, Eva; Wacheck, Volker (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. 
  53. ^ 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. 
  54. ^ 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
  55. ^ http://www.nasdaq.com/article/curis-achieves-cudc-907-milestones-under-its-agreement-with-the-leukemia--lymphoma-society-20121018-00214
  56. ^ 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]