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] both alone and in combination.[11]

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

Effects of inhibiting different isoforms

Inhibiting different p110 isoforms can have different effects.[12] e.g. PTEN-negative tumors may be more sensitive to p110β inhibitors.[12]

Notable examples

  • Wortmannin: an irreversible inhibitor of PI3K.
  • LY294002:[6] a reversible inhibitor of PI3K.
  • hibiscone C: an irreversible inhibitor of PI3K.

Approvals

  • Idelalisib (PI3K Delta inhibitor) FDA approved July 2014 for relapsed or refractory chronic lymphocytic leukemia (CLL) in combination with rituximab, relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies, and 3rd line follicular lymphoma in patients who have received at least two prior systemic therapies.[13]
  • Copanlisib (Inhibitor of PI3K, predominantly against PI3K-α and PI3K-δ) FDA approved in September 2017 for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.[14]
  • Duvelisib (an oral dual inhibitor of PI3K-delta and PI3K-gamma) FDA approved duvelisib on September 24, 2018. Duvelisib is approved for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies, and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies.[15]
  • Alpelisib (BYL719), an alpha-specific PI3K inhibitor,[16] approved by the FDA in May 2019 for use in combination with endocrine therapy fulvestrant for treatment of HR-positive and HER2/neu-negative breast cancer.[17]
  • Umbralisib was approved for medical use in the United States in February 2021.[18][19] Umbralisib is indicated for adults with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen; and adults with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.[18][20]

Clinical development

Late stage

In phase III clinical trials:

In/starting phase II clinical trials:

Early stage

With phase I results announced :

In early stage clinical trials[10]

  • RP6530, Dual PI3K delta/gamma inhibitor for lymphomas.[55]
  • INK1117, a PI3K-alpha inhibitor in phase I.[56]
  • pictilisib[57] (GDC-0941)[58][59][60] IC50 of 3nM.
  • XL147 (also known as SAR245408)[61]
  • Palomid 529[62]
  • GSK1059615 The phase I trial of this drug was terminated due to lack of sufficient exposure following single- and repeat- dosing.[63]
  • ZSTK474,[64] a potent inhibitor against p110a.
  • PWT33597, a dual PI3K-alpha/mTOR inhibitor – for advanced solid tumors.[65] IND mid 2011.[66] Phase I recruiting.[67]

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[68]
  • RP6503, Dual PI3K delta/gamma inhibitor for the treatment of Asthma and COPD (Late pre-clinical stage).[69][70]
  • PI-103[71] Dual PI3K-mTOR inhibitor.[72]
  • GNE-477 is PI3K-alpha and mTOR inhibitor with IC50 values of 4nM and 21nM.
  • AEZS-136, also inhibits Erk1/2.[73]

See also

References

  1. ↑ Kurtz JE, Ray-Coquard I (July 2012). "PI3 kinase inhibitors in the clinic: an update". Anticancer Research. 32 (7): 2463–70. PMID 22753702.
  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, et al. (January 2003). "The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells". Molecular Cancer Research. 1 (3): 234–46. PMID 12556562.
  4. 1 2 Ito K, Caramori G, Adcock IM (April 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. S2CID 1906947.
  5. ↑ Study results provide rationale for use of PI3K inhibitors in therapeutic settings. News-medical.net. Retrieved on 2010-11-05.
  6. 1 2 3 4 Crabbe T (April 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 RC (September 2001). "Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment". Endocrine-Related Cancer. 8 (3): 237–48. CiteSeerX 10.1.1.324.8135. doi:10.1677/erc.0.0080237. PMID 11566615.
  8. ↑ Flanagan (Dec 2008). "Zeroing in on PI3K Pathway". Archived from the original on 2013-01-24.
  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. 1 2 Maira SM, Stauffer F, Schnell C, García-Echeverría C (February 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. ↑ Heavey S, O'Byrne KJ, Gately K (April 2014). "Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC". Cancer Treatment Reviews. 40 (3): 445–56. doi:10.1016/j.ctrv.2013.08.006. PMID 24055012.
  12. 1 2 Edgar, Kyle A.; Wallin, Jeffrey J.; Berry, Megan; Lee, Leslie B.; Prior, Wei Wei; Sampath, Deepak; Friedman, Lori S.; Belvin, Marcia (1 February 2010). "Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors". Cancer Research. 70 (3): 1164–1172. doi:10.1158/0008-5472.CAN-09-2525. PMID 20103642.
  13. ↑ "FDA approves Zydelig for three types of blood cancers". US Food and Drug Administration. July 23, 2014.
  14. ↑ "FDA approves new treatment for adults with relapsed follicular lymphoma". US Food and Drug Administration. September 14, 2017.
  15. ↑ "FDA Approval for duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)". US Food and Drug Administration. September 24, 2018.
  16. ↑ Novel Agents Show Promise Against Endocrine-resistant Breast Cancer. July 2016
  17. ↑ "FDA approves first PI3K inhibitor for breast cancer". Food and Drug Administration. 2019-05-24.
  18. 1 2 "FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma". U.S. Food and Drug Administration (FDA). 5 February 2021. Retrieved 5 February 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  19. ↑ "TG Therapeutics Announces FDA Accelerated Approval of Ukoniq (umbralisib)" (Press release). TG Therapeutics. 5 February 2021. Retrieved 5 February 2021 – via GlobeNewswire.
  20. ↑ "Ukoniq (umbralisib) tablets, for oral use" (PDF). TG Therapeutics.
  21. ↑ "Search of: CAL101 – List Results – ClinicalTrials.gov". clinicaltrials.gov.
  22. ↑ Wu M, Akinleye A, Zhu X (May 2013). "Novel agents for chronic lymphocytic leukemia". Journal of Hematology & Oncology. 6: 36. doi:10.1186/1756-8722-6-36. PMC 3659027. PMID 23680477.
  23. ↑ EMA Article 20 procedure for Idelalisib
  24. ↑ Clinical trial number NCT02536300 for "Dose Optimization Study of Idelalisib in Follicular Lymphoma" at ClinicalTrials.gov
  25. ↑ Clinical trial number NCT01068483 for "Safety of BKM120 Monotherapy in Advanced Solid Tumor Patients" at ClinicalTrials.gov
  26. ↑ Clinical trial number NCT01132664 for "Phase 1b/2 Study of BKM120 Plus Trastuzumab in Patients With HER2-positive Breast Cancer" at ClinicalTrials.gov
  27. ↑ Johnson, Kate (14 December 2015). "PI3K Inhibitor Penetrates Endocrine-Resistant Breast Cancer". Medscape Medical News.
  28. ↑ "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". finanznachrichten.de. 31 October 2011.
  29. ↑ "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". Retrieved November 28, 2011.
  30. ↑ Bayer to Present New Data on Growing Oncology Pipeline. April 2013 Archived 2013-04-14 at the Wayback Machine
  31. ↑ "Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL. March 2016". Archived from the original on 2016-04-05. Retrieved 2016-03-22.
  32. ↑ Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT (September 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.
  33. ↑ PX-866 June 2010
  34. ↑ Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
  35. ↑ "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 Nov 2010.
  36. ↑ Liu TJ, Koul D, LaFortune T, Tiao N, Shen RJ, Maira SM, et al. (August 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.
  37. ↑ 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
  38. ↑ Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, et al. (October 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.
  39. 1 2 Clinical trial number NCT03002623 for "CUDC-907 Treatment in People With Metastatic and Locally Advanced Thyroid Cancer" at ClinicalTrials.gov
  40. ↑ Voxtalisib for CLL and B-Cell Lymphomas March 2018
  41. ↑ Clinical trial number NCT01403636 for "A Study of Investigational SAR245409 in Patients With Certain Lymphoma or Leukemia" at ClinicalTrials.gov
  42. ↑ Business Wire (2011-11-16). "Curis Presents Data On PI3K And HDAC Inhibitor CUDC-907 At The 2011 AACR-NCI-EORTC Symposium". TheStreet.
  43. ↑ Novel Dual HDAC/PI3K Inhibitor Assessed in Lymphoma, Myeloma. April 2016
  44. ↑ Dual HDAC, PI3K Inhibitor Active in Lymphoma, Myeloma. April 2016
  45. ↑ New PI3K Delta Inhibitor to Treat Blood Cancers Shows Promise in Early Clinical Study May 2, 2016. Ines Martins Archived May 6, 2016, at the Wayback Machine
  46. ↑ Infinity Provides Company Update... May 2016
  47. ↑ IPI-549 early clinical. Sept 2016
  48. ↑ Definition of pan-PI3K/mTOR inhibitor SF1126 – National Cancer Institute Drug Dictionary. Cancer.gov. Retrieved on 2010-11-05.
  49. ↑ "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.
  50. ↑ 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
  51. ↑ Semafore's SF1126 peptidic prodrug demonstrates clinical activity in chronic lymphocytic leukemia. News-medical.net. Retrieved on 2010-11-05.
  52. ↑ Update on the Novel Prodrug Dual mTOR‐PI3K Inhibitor SF1126 Archived 2011-07-16 at the Wayback Machine
  53. ↑ Semafore Pharmaceuticals. "Semafore Pharmaceuticals Announces Presentation Highlighting Activity of Multi-Kinase, PI3K/mTOR Inhibitor SF1126 at 2011 AACR Annual Meeting". GlobeNewswire News Room.
  54. ↑ "Semafore Pharmaceuticals Receives FDA Orphan Drug Designation for SF1126 in the Treatment of Chronic Lymphocytic Leukemia". 9 Nov 2010.
  55. ↑ Rhizen Pharmaceuticals SA (6 December 2013). "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.
  56. ↑ "Intellikine commences INK1117 Phase I dose escalation study in cancer". 12 Oct 2011.
  57. ↑ Sarker D, Ang JE, Baird R, Kristeleit R, Shah K, Moreno V, et al. (January 2015). "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". Clinical Cancer Research. 21 (1): 77–86. doi:10.1158/1078-0432.CCR-14-0947. PMC 4287394. PMID 25370471.
  58. ↑ 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
  59. ↑ Clinical trial number NCT00876109 for "A Study of GDC-0941 in Participants With Locally Advanced or Metastatic Solid Tumors for Which Standard Therapy Either Does Not Exist or Has Proven Ineffective or Intolerable" at ClinicalTrials.gov
  60. ↑ 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
  61. ↑ Clinical trial number NCT01042925 for "Study of XL147 (SAR245408) in Combination With Trastuzumab or Paclitaxel and Trastuzumab in Subjects With Metastatic Breast Cancer Who Have Progressed on a Previous Trastuzumab-based Regimen" at ClinicalTrials.gov
  62. ↑ Clinical trial number NCT01033721 for "Phase I Study of Palomid 529 a Dual TORC1/2 Inhibitor of the PI3K/Akt/mTOR Pathway for Advanced Neovascular Age-Related Macular Degeneration (P52901)" at ClinicalTrials.gov
  63. ↑ "GSK Clinical Register: PIK111051". Archived from the original on 2012-07-12.
  64. ↑ Clinical trial number NCT01280487 for "A Safety Study of Oral ZSTK474 in Patients With Cancer" at ClinicalTrials.gov
  65. ↑ Pathway Receives $7.5M Boost to Take Lead PI3K/mTOR Inhibitor into Clinical Development. 25 May 2011
  66. ↑ "Archived copy". Archived from the original on 2011-07-25. Retrieved 2011-06-01.{{cite web}}: CS1 maint: archived copy as title (link)
  67. ↑ "Pathway Therapeutics Announces Appointment of Mark Perry and Dr. Paul Goddard to its Board of Directors – Business Wire". businesswire.com. 15 August 2011.
  68. ↑ Clinical trial number NCT01066611 for "Study to Investigate Effects of CAL-263 in Subjects With Allergic Rhinitis Exposed to Allergen in an Environmental Chamber" at ClinicalTrials.gov
  69. ↑ http://rhizen.com/News%20&%20PR/Rhizen_Press%20Release_ATS_May'13.pdf%5B%5D
  70. ↑ Vakkalanka, Swaroop; Routhu, Kasiviswanath; Govindarajulu, Babu; Veeraraghavan, Sridhar; Nagarathnam, Dhanapalan; Viswanadha, Srikant (1 May 2013). "Preclinical Efficacy Of RP6503, A Novel, Dual PI3Kδ/? Inhibitor In Airway Disorders". C23. Novel Therapeutics in Asthma. American Thoracic Society International Conference Abstracts: A3880. doi:10.1164/ajrccm-conference.2013.187.1_meetingabstracts.a3880 (inactive 31 October 2021).{{cite journal}}: CS1 maint: DOI inactive as of October 2021 (link)
  71. ↑ Werzowa J, Koehrer S, Strommer S, Cejka D, Fuereder T, Zebedin E, Wacheck V (February 2011). "Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo". The Journal of Investigative Dermatology. 131 (2): 495–503. doi:10.1038/jid.2010.327. PMC 3016554. PMID 21048785.
  72. ↑ Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, et al. (November 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.
  73. ↑ 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 R, Berndt A, Miller S, Hon WC, Zhang X (August 2009). "Form and flexibility in phosphoinositide 3-kinases". Biochemical Society Transactions. 37 (Pt 4): 615–26. doi:10.1042/BST0370615. PMID 19614567.
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