Phosphoinositide 3-kinase inhibitor
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. 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.
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.
- Wortmannin an irreversible inhibitor of PI3K.
- demethoxyviridin a derivative of wortmannin.
- LY294002 a reversible inhibitor of PI3K.
- Perifosine, for colorectal cancer and multiple myeloma.
- Idelalisib an oral PI3K delta inhibitor for chronic lymphocytic leukaemia.
In/starting phase II clinical trials:
- PX-866 In 2010 Starting 4 phase II trials for solid tumours.
- IPI-145, a novel inhibitor of PI3K delta and gamma, especially for hematologic malignancies (currently in two Phase 1 clinical trials in hematologic cancers as well as a broad range of inflammatory conditions). July 2012 the phase I trial was expanded and two phase II trials are planned, OK at 75 mg BID, will try 100 mg BID. Also in phase 2a for asthma.
- BAY 80-6946, predominantly inhibits PI3Kα,δ isoforms.
In early stage clinical trials 
- BEZ235 The first into clinical trials, in 2006. A PI3K/mTOR dual inhibitor.
- RP6530, Dual PI3K delta/gamma inhibitor for lymphomas. 
- TGR 1202, oral PI3K delta inhibitor (previously known as RP5264). Phase I recruiting 
- SF1126 Some early clinical data has been presented. First PI3KI 'Orphan Drug' for B-cell chronic lymphocytic leukemia (CLL).
- INK1117, a PI3K-alpha inhibitor in phase I.
- 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.
- IC87114 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.
- 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.
- CUDC-907, Also an HDAC inhibitor. IND has been filed.
- AEZS-136, also inhibits Erk1/2.
- PI3K/AKT/mTOR pathway for inhibitors of AKT and mTOR downstream from PI3K
- Kurtz J.E. Ray-Coquard I., 2012. PI3 kinase inhibitors in the clinic: an update. [Review]. Anticancer Research, 32(7), pp.2463-70
- [http://www.bioportfolio.com/LeadDiscovery/PubMed-030301.html[dead link] "PI3K inhibitors: Targeting multiple tumor progression pathways"]. 2003.
- 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.
- 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.
- 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".
- 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.
- 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
- 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.
- 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.
- "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". 31 Oct 2011.
- "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". Retrieved November 28, 2011.
- "Infinity Regains Worldwide Rights to PI3K, FAAH and Early Discovery Programs". 18 July 2012.
- Infinity Reports IPI-145 Phase 1 Data Showing Clinical Activity in B-Cell and T-Cell Malignancies at ASH Annual Meeting. Dec 2012
- Bayer to Present New Data on Growing Oncology Pipeline. April 2013
- 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.
- ClinicalTrials.gov NCT00620594 A Phase I/II Study of BEZ235 in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer
- 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.
- 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. 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
- "Semafore Pharmaceuticals Receives FDA Orphan Drug Designation for SF1126 in the Treatment of Chronic Lymphocytic Leukemia". 9 Nov 2010.
- "Intellikine commences INK1117 Phase I dose escalation study in cancer". 12 Oct 2011.
- 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
- ClinicalTrials.gov NCT00485719
- ClinicalTrials.gov NCT01033721
- "GSK Clinical Register: PIK111051".
- 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://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". Journal of Investigative Dermatology 131 (2): 495–503. doi:10.1038/jid.2010.327. PMID 21048785.
- 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.
- 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.