Phosphoinositide 3-kinase inhibitor

A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a 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

• 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

In phase III clinical trials:

• Perifosine, for colorectal cancer and multiple myeloma. (discontinued 2013)
• Idelalisib^[12] also for chronic lymphocytic leukaemia.^[13] Trials for CLL terminated/abandoned in 2015.
• Idelalisib for indolent non-Hodgkin lymphoma.^[14]
• Buparlisib (BKM120)^[15][16] for HR+/HER2 advanced endocrine-resistant breast cancer - encouraging results in Dec 2015.^[17]
• Duvelisib, (IPI-145) a novel inhibitor of PI3K delta and gamma,^[18] especially for hematologic malignancies and inflammatory conditions.^[19] It is in 4 active phase 3 trials.
• Alpelisib (BYL719), an alpha-specific PI3K inhibitor,^[20] starting SOLAR-1 trial for PIK3CA-altered metastatic breast cancer.^[21] Trial to end July 2019.^[22]
• TGR 1202, oral PI3K delta inhibitor (previously known as RP5264).^[23] "has shown promising efficacy with a superior toxicity profile compared with idelalisib"^[14] Now in ph3 for CLL.^[24] 3 year data (inc Follicular Lymphoma and DLBCL) announced June 2016.^[25] Once daily administration.
• Copanlisib (BAY 80-6946), predominantly inhibits PI3Kα,δ isoforms.^[26] for indolent non-Hodgkin lymphoma.^[14]

In/starting phase II clinical trials:

• PX-866^[27][28][29] In 2010 Starting 4 phase II trials for solid tumours.^[30] Mixed results since 2012.

Early stage

In early stage clinical trials ^[10]

• Dactolisib^[31] The first into clinical trials, in 2006.^[32] A PI3K/mTOR dual inhibitor.^[33]
• RP6530, Dual PI3K delta/gamma inhibitor for lymphomas.^[34]
• SF1126^[35][36][37] Some early clinical data has been presented.^[38][39][40] First PI3KI 'Orphan Drug' for B-cell chronic lymphocytic leukemia (CLL).^[41] SF1126 is the first PI-3 kinase inhibitor to enter pediatric cancer clinical trials via the NANT consortium.
• INK1117, a PI3K-alpha inhibitor in phase I.^[42]
• pictilisib^[43] (GDC-0941)^[44][45][46] IC50 of 3nM.
• XL147 (also known as SAR245408)^[47]
• XL765 (also known as SAR245409)^[48]
• Palomid 529^[49]
• GSK1059615 The phase I trial of this drug was terminated due to lack of sufficient exposure following single- and repeat- dosing.^[50]
• ZSTK474,^[51] a potent inhibitor against p110a.
• PWT33597, a dual PI3K-alpha/mTOR inhibitor - for advanced solid tumors.^[52] IND mid 2011.^[53] Phase I recruiting.^[54]
• CUDC-907, Also an HDAC inhibitor.^[55] IND has been filed.^[56] In 2016 it was reported as showing promising preliminary evidence of response in patients with diffuse large B-cell lymphoma.^[57][58]
• ME-401, PI3K-Delta Inhibitor.^[59]
• IPI-549, a PI3K-gamma inhibitor, in phase 1 for various cancers.^[60]

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^[61]
• RP6503,Dual PI3K delta/gamma inhibitor for the treatment of Asthma and COPD (Late pre-clinical stage).^[62][63]
• PI-103^[64] Dual PI3K-mTOR inhibitor.^[65]
• GNE-477 is PI3K-alpha and mTOR inhibitor with IC50 values of 4nM and 21nM.
• AEZS-136, also inhibits Erk1/2.^[66]

See also

• PI3K/AKT/mTOR pathway for inhibitors of AKT and mTOR downstream from PI3K
• P110δ#Pharmacology, P110δ (PI3K-delta) as a drug target

References

1. Kurtz, J.E.; Ray-Coquard, I. (2012). "PI3 kinase inhibitors in the clinic: an update. [Review]". Anticancer Research. 32 (7): 2463–70.
2. "PI3K inhibitors: Targeting multiple tumor progression pathways". 2003. Archived from the original on February 28, 2009.
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. 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. 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. 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. "Search of: CAL101 - List Results - ClinicalTrials.gov". clinicaltrials.gov.
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.
14. Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016
15. Clinical trial number NCT01068483 at ClinicalTrials.gov
16. Clinical trial number NCT01132664 at ClinicalTrials.gov
17. PI3K Inhibitor Penetrates Endocrine-Resistant Breast Cancer. Dec 2015
18. "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". finanznachrichten.de. 31 October 2011.
19. "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". Retrieved November 28, 2011.
20. Novel Agents Show Promise Against Endocrine-resistant Breast Cancer. July 2016
21. Alpelisib Combo Promising in PIK3CA-Altered, Heavily Pretreated Breast Cancer. March 2016
22. Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment. (SOLAR-1)
23. "Evaluate the Safety and Efficacy of TGR 1202 in Patients With Relapsed or Refractory Hematologic Malignancies". clinicaltrials.gov.
24. Therapy Focus - TG Could Benefit From Zydelig Setback. March 2016
25. TG Therapeutics Inc.: TG Therapeutics, Inc. Announces First Patient Enrolled in the Registration-Directed UNITY-DLBCL Phase 2b Trial. June 2016
26. Bayer to Present New Data on Growing Oncology Pipeline. April 2013
27. 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.
28. PX-866 June 2010
29. Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
30. "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 Nov 2010.
31. 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.
32. 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
33. Serra, V; Markman, B; Scaltriti, M; Eichhorn, PJA; Valero, V; Guzman, M; Botero, ML; Llonch, E (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.
34. Rhizen Pharmaceuticals SA. "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". GlobeNewswire News Room.
35. Definition of pan-PI3K/mTOR inhibitor SF1126 - National Cancer Institute Drug Dictionary. Cancer.gov. Retrieved on 2010-11-05.
36. "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.
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38. Semafore's SF1126 peptidic prodrug demonstrates clinical activity in chronic lymphocytic leukemia. News-medical.net. Retrieved on 2010-11-05.
39. Update on the Novel Prodrug Dual mTOR‐PI3K Inhibitor SF1126
40. Semafore Pharmaceuticals. "Semafore Pharmaceuticals Announces Presentation Highlighting Activity of Multi-Kinase, PI3K/mTOR Inhibitor SF1126 at 2011 AACR Annual Meeting". GlobeNewswire News Room.
41. "Semafore Pharmaceuticals Receives FDA Orphan Drug Designation for SF1126 in the Treatment of Chronic Lymphocytic Leukemia". 9 Nov 2010.
42. "Intellikine commences INK1117 Phase I dose escalation study in cancer". 12 Oct 2011.
43. First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Jan 2015
44. 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
45. Clinical trial number NCT00876109 at ClinicalTrials.gov
46. 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
47. Clinical trial number NCT01042925 at ClinicalTrials.gov
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51. A Safety Study of Oral ZSTK474 in Patients With Cancer
52. Pathway Receives $7.5M Boost to Take Lead PI3K/mTOR Inhibitor into Clinical Development. 25 May 2011
53. 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
54. "Pathway Therapeutics Announces Appointment of Mark Perry and Dr. Paul Goddard to its Board of Directors - Business Wire". businesswire.com. 15 August 2011.
55. Business Wire. "Curis Presents Data On PI3K And HDAC Inhibitor CUDC-907 At The 2011 AACR-NCI-EORTC Symposium". TheStreet.
56. "Today's Stock Market News and Analysis - Nasdaq.com". NASDAQ.com.
57. Novel Dual HDAC/PI3K Inhibitor Assessed in Lymphoma, Myeloma. April 2016
58. Dual HDAC, PI3K Inhibitor Active in Lymphoma, Myeloma. April 2016
59. New PI3K Delta Inhibitor to Treat Blood Cancers Shows Promise in Early Clinical Study May 2, 2016. Ines Martins
60. Infinity Provides Company Update... May 2016
61. Study to Investigate Effects of CAL-263 in Subjects With Allergic Rhinitis Exposed to Allergen in an Environmental Chamber
62. http://rhizen.com/News%20&%20PR/Rhizen_Press%20Release_ATS_May'13.pdf
63. http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2013.187.1_MeetingAbstracts.A3880
64. "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. 4 November 2010. doi:10.1038/jid.2010.327. PMID 21048785.
65. Fan (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.
66. 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

• 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

• Novartis on BEZ235 and BKM120 PI3K inhibitors