Phosphoinositol-3-kinase (PI3K) inhibitors based on 1,3,5-triazine derivatives for targeted antitumor therapy
https://doi.org/10.24884/1607-4181-2025-32-3-42-52
Abstract
Phosphoinositol-3-kinases (PI3K) may be considered as targets for targeted therapy of tumors. The 1,3,5-triazine core is considered the promising scaffold in antitumor drug development, that affect to various targets in tumor cells. This review examines 1,3,5-triazine derivatives (s-triazine) with strong inhibitory activity against PI3K kinases. Moreover, the key structural fragments that play a crucial role in binding to the active sites of PI3K are summarized. The prospects of developing bifunctional agents, which simultaneously affect two or more targets within the same or different signaling pathways, are also discussed.
About the Authors
I. S. Chernov
Pavlov University
Russian Federation
Competing Interests:
Russian Federation
Chernov Ivan S., Postgraduate Student of the Department of General and Bioorganic Chemistry
6-8, L’va Tolstogo str., Saint Petersburg, 197022
Competing Interests:
Authors declare no conflict of interest.
E. A. Popova
Pavlov University
Russian Federation
Competing Interests:
Russian Federation
Popova Еlena А., Dr. of Sci. (Chem.), Professor of the Department of General and Bioorganic Chemistry
6-8, L’va Tolstogo str., Saint Petersburg, 197022
Competing Interests:
Authors declare no conflict of interest.
A. V. Protas
Pavlov University
Russian Federation
Competing Interests:
Russian Federation
Protas Aleksandra V., Cand. of Sci. (Chem.), Associate Professor of the Department of General and Bioorganic Chemistry
6-8, L’va Tolstogo str., Saint Petersburg, 197022
Competing Interests:
Authors declare no conflict of interest.
O. E. Molchanov
A. M. Granov Russian Research Centre for Radiology and Surgical Technologies
Russian Federation
Competing Interests:
Russian Federation
Molchanov Oleg E., Dr. of Sci. (Med.), Head of the Department of Fundamental Researches
70, Leningradskaya str., Saint Petersburg, Pesochny settlement, 197758
Competing Interests:
Authors declare no conflict of interest.
V. V. Sharoyko
Pavlov University; St. Petersburg State University
Russian Federation
Competing Interests:
Russian Federation
Sharoyko Vladimir V., Dr. of Sci. (Biol.), Professor of the Department of General and Bioorganic Chemistry; Leading Research Fellow of the Department of Solid State Chemistry, Institute of Chemistry
6-8, L’va Tolstogo str., Saint Petersburg, 197022
7-9 Universitetskaya Embankment, Saint Petersburg, 199034
Competing Interests:
Authors declare no conflict of interest.
K. N. Semenov
Pavlov University; St. Petersburg State University
Russian Federation
Competing Interests:
Russian Federation
Semenov Konstantin N., Dr. of Sci. (Chem.), Professor of the Department of General and Bioorganic Chemistry; Professor of the Department of Solid State Chemistry, Institute of Chemistry
6-8, L’va Tolstogo str., Saint Petersburg, 197022
7-9 Universitetskaya Embankment, Saint Petersburg, 199034
Competing Interests:
Authors declare no conflict of interest.
References
1. Zhong L., Li Y., Xiong L. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives // Signal Transduction and Targeted Therapy. – 2021. – Vol. 6, № 1. – P. 201. https://doi.org/10.1038/s41392-021-00572-w.
2. Korman D. B. Targets and mechanisms of action of antitumor drugs. Moscow, Practical medicine, 2014. 333 p. (In Russ.).
3. Lee S. Y., Oh S. C. Changing strategies for target therapy in gastric cancer // World Journal of Gastroenterology. – 2016. – Vol. 22, № 3. – P. 1179–1189. https://doi.org/10.3748/WJG.V22.I3.1179.
4. Valerio L., Pieruzzi L., Giani C. et al. Targeted Therapy in Thyroid Cancer: State of the Art // Clinical Oncology. – 2017. – Vol. 29, № 5. – P. 316–324. https://doi.org/10.1016/J.CLON.2017.02.009.
5. Min H. Y., Lee H. Y. Molecular targeted therapy for anticancer treatment // Experimental and Molecular Medicine. – 2022. – Vol. 54. – P. 1670–1694. https://doi.org/10.1038/s12276-022-00864-3.
6. Yu M., Chen J., Xu Z. et al. Development and safety of PI3K inhibitors in cancer // Archives of Toxicology. – 2023. – Vol. 97. – P. 635–650. https://doi.org/10.1007/s00204-02303440-4.
7. Liu P., Cheng H., Roberts T. M., Zhao J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Reviews Drug Discovery. – 2009. – Vol. 8. – P. 627–644. https://doi.org/10.1038/nrd2926.
8. Vanhaesebroeck B., Perry M. W. D., Brown J. R. et al. PI3K inhibitors are finally coming of age. Nature Reviews Drug Discovery. – 2021. – Vol. 20. – P. 741–769. https://doi.org/10.1038/s41573-021-00209-1.
9. Occhiuzzi M. A., Lico G., Ioele G. et al. Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents // European Journal of Medicinal Chemistry. – 2023. – Vol. 246. – P. 114971. https://doi.org/10.1016/j.ejmech.2022.114971.
10. Sirico M., D’Angelo A., Gianni C. et al. Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy // Cancers. – 2023. – Vol. 15, № 3. – P. 703. https://doi.org/10.3390/cancers15030703.
11. Mansour M., Lasheen D., Gaber H., Abouzid K. Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer // RSC Advances. – 2020. – Vol. 10. – P. 32103–32112. https://doi.org/10.1039/D0RA06428A.
12. Naeem M., Iqbal M. O., Khan H. et al. A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer // Molecules. – 2022. – Vol. 27, № 11. – P. 3412. https://doi.org/10.3390/molecules27113412.
13. Xian Q., Zhu D. The Involvement of WDHD1 in the Occurrence of Esophageal Cancer as a Downstream Target of PI3K/AKT Pathway // Journal of Oncology. – 2022. – Vol. 2022. – 871188. https://doi.org//10.1155/2022/5871188.
14. Di Blasio L., Gagliardi P. A., Puliafito A., Primo L. Serine/threonine kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) as a key regulator of cell migration and cancer dissemination // Cancers. – 2017. – Vol. 9, № 3. – P. 25. https://doi.org/10.3390/cancers9030025.
15. Samuels Y., Wang Z., Bardelli A. et al. High Frequency of Mutations of the PIK3CA Gene in Human Cancers // Science. – 2004. – Vol. 304, № 5670. – P. 554. https://doi.org/10.1126/science.1096502.
16. Glaviano A., Foo A., Lam H. et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer // Molecular Cancer. – 2023. – Vol. 22. – P. 138. https:// doi.org/10.1186/s12943-023-01827-6.
17. Asati V., Mahapatra D. K., Bharti S. K. PI3K/Akt/ mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives // European Journal of Medicinal Chemistry. – 2016. – Vol. 109. – P. 314–341. https://doi.org/10.1016/j.ejmech.2016.01.012.
18. Ellis H., Ma C. X. PI3K Inhibitors in Breast Cancer Therapy // Current Oncology Reports. – 2019. – Vol. 21. – P. 110. https://doi.org/10.1007/s11912-019-0846-7.
19. Castel P., Toska E., Engelman J. A., Scaltriti M. The present and future of PI3K inhibitors for cancer therapy // Nature Cancer. – 2021. – Vol. 2. – P. 587–597. https://doi.org/10.1038/s43018-021-00218-4.
20. Faes S., Demartines N., Dormond O. Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity // Oxidative Medicine and Cellular Longevity. – 2017. – Vol. 2017. – P. 1726078. https://doi.org/10.1155/2017/1726078.
21. Fan Q. W., Knight Z. A., Goldenberg D. D. et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma // Cancer Cell. – 2006. – Vol. 9, № 5. – P. 341–349. https://doi.org/10.1016/j.ccr.2006.03.029.
22. Wang H. Y., Shen Y., Zhang H. et al. Discovery of 2-(aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6- substituted triazine as PI3K and BRAF dual inhibitor // Future Medicinal Chemistry. – 2018. – Vol. 10, № 20. – P. 2445–2455. https://doi.org/10.4155/fmc-2018-0145.
23. Dai Q., Sun Q., Ouyang X. et al. Antitumor Activity of s-Triazine Derivatives: A Systematic Review // Molecules. – 2023. – Vol. 28, № 11. – P. 4278. https://doi.org/10.3390/ molecules28114278.
24. Rathod B., Pawar S., Puri S. et al. Recent Advancements and Developments in the Biological Importance of 1,3,5-Triazines // ChemistrySelect. – 2024. – Vol. 9, № 12. – e202303655. https://doi.org/10.1002/slct.202303655.
25. Dong G., Jiang Y., Zhang F. et al. Recent updates on 1,2,3-, 1,2,4-, and 1,3,5-triazine hybrids (2017–present): The anticancer activity, structure–activity relationships, and mechanisms of action // Archiv der Pharmazie. – 2023. – Vol. 356, № 3. – 2200479. https://doi.org/10.1002/ardp.202200479.
26. Dubey P., Pathak D. P., Ali F. et al. In-vitro Evaluation of Triazine Scaffold for Anticancer Drug Development: A Review // Current Drug Discovery Technologies. – 2023. – Vol. 21, № 2. – 2200479. https://doi.org/10.2174/1570163820666230717161610.
27. Gangasani J. K., Yarasi S., Naidu V. G. M., Vaidya J. R. Triazine based chemical entities for anticancer activity // Physical Sciences Reviews. – 2023. – Vol. 8, № 10. – P. 3545– 3575. https://doi.org/10.1515/psr-2022-0005.
28. Maliszewski D., Drozdowska D. Recent Advances in the Biological Activity of s-Triazine Core Compounds // Pharmaceuticals. – 2022. – Vol. 15, № 2. – P. 221. https:// doi.org/10.3390/ph15020221.
29. Singla P., Luxami V., Paul K. Triazine as a promising scaffold for its versatile biological behavior // European Journal of Medicinal Chemistry. – 2015. – Vol. 102. – P. 39–57. https://doi.org/10.1016/j.ejmech.2015.07.037.
30. Liu B. A Systematic Review on Antitumor Agents with 1, 3, 5-triazines // Medicinal Chemistry. – 2015. – Vol. 5, № 3. – P. 131–148. https://doi.org/10.4172/2161-0444.1000255.
31. Lim H. Y., Dolzhenko A. V. 1,3,5-Triazine as a promising scaffold in the development of therapeutic agents against breast cancer // European Journal of Medicinal Chemistry. – 2024. – Vol. 276. – 116680. https://doi.org/10.1016/j.ejmech.2024.116680.
32. Ali M. I., Naseer M. M. Recent biological applications of heterocyclic hybrids containing s-triazine scaffold // RSC Advances. – 2023. – Vol. 13. – P. 30462–30490. https://doi.org/10.1039/d3ra05953g.
33. Karataş Ö., Ceylan Y., Koc Z. 2,4,6-Tris(p-aminoanilino)-1,3,5-triazine: Synthesis and Electron Paramagnetic Resonance (EPR) Analysis // Sakarya University Journal of Science. – 2022. – Vol. 26. – P. 1170–1179. https://doi.org/10.16984/saufenbilder.1135112.
34. Sonawane R. P., Sikervar V., Sasmal S. 1,3,5-Triazines // Comprehensive Heterocyclic Chemistry IV. – 2022. – Vol. 9. – P. 181–283. https://doi.org/10.1016/B9780-12-818655-8.00018-4.
35. Wang Y., Tortorella M. Molecular design of dual inhibitors of PI3K and potential molecular target of cancer for its treatment: A review // European Journal of Medicinal Chemistry. – 2022. – Vol. 228. – P. 114039. https://doiorg/10.1016/j.ejmech.2021.114039.
36. Rewcastle G. W., Gamage S. A., Flanagan J. U. et al. Synthesis and biological evaluation of novel analogues of the pan class i phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(Difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1 H -benzimidazole (ZSTK474) // Journal of Medicinal Chemistry. – 2011. – Vol. 54, № 20. – P. 7105–7126. https://doi.org/10.1021/jm200688y.
37. Yaguchi S. I., Fukui Y., Koshimizu I. et al. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor // Journal of the National Cancer Institute. – 2006. – Vol. 98, № 8. – P. 545–556. https://doi.org/10.1093/jnci/djj133.
38. Wang Y., Liu Y., Ge T. et al. Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors // Bioorganic Chemistry. – 2023. – Vol. 130. – P. 106211. https://doi.org/10.1016/j.bioorg.2022.106211.
39. Smith A. L., D’Angelo N. D., Bo Y. Y. et al. Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases // Journal of Medicinal Chemistry. – 2012. – Vol. 55, № 11. – P. 5188–5219. https://doi.org/10.1021/jm300184s.
40. Venkatesan A. M., Dehnhardt C. M., Delos Santos E. et al. Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound 26 (PKI-587), a Highly Efficacious Dual Inhibitor // Journal of Medicinal Chemistry. – 2010. – Vol. 53, № 6. – P. 2636–2645. https://doi.org/10.1021/jm901830p.
41. Rossetti S., Broege A., Sen A. et al. Gedatolisib shows superior potency and efficacy versus single-node PI3K/AKT/ mTOR inhibitors in breast cancer models // NPJ Breast Cancer. – 2024. – Vol. 10, № 1. – P. 40. https://doi.org/10.1038/s41523-024-00648-0.
42. Venkatesan A. M., Chen Z., dos Santos O. et al. PKI179: An orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor // Bioorganic & Medicinal Chemistry Letters. – 2010. – Vol. 20, № 19. – P. 5869–5873. https://doi.org/10.1016/j.bmcl.2010.07.104.
43. Wu T. T., Guo Q. Q., Chen Z. L. et al. Design, synthesis and bioevaluation of novel substituted triazines as potential dual PI3K/mTOR inhibitors // European Journal of Medicinal Chemistry. – 2020. – Vol. 204. – P. 112637. https://doi.org/10.1016/j.ejmech.2020.112637.
44. Andrs M., Korabecny J., Jun D. et al. Phosphatidylinositol 3-kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: Importance of the morpholine ring // Journal of Medicinal Chemistry. – 2015. – Vol. 58, № 1. – P. 41–71. https://doi.org/10.1021/jm501026z.
45. Doogue M. P., Polasek T. M. The ABCD of clinical pharmacokinetics // Therapeutic Advances in Drug Safety. – 2013. – Vol. 4, № 1. – P. 5–7. https://doi.org/10.1177/2042098612469335.
46. Dugar S., Hollinger F. P., Mahajan D. et al. Discovery of Novel and Orally Bioavailable Inhibitors of PI3 Kinase Based on Indazole Substituted Morpholino-Triazines // ACS Medicinal Chemistry Letters. – 2015. – Vol. 6, № 12. – P. 1190–1194. https://doi.org/10.1021/acsmedchemlett.5b00322.
47. Collins G. P., Eyre T. A., Schmitz-Rohmer D. et al. A Phase II Study to Assess the Safety and Efficacy of the Dual mTORC1/2 and PI3K Inhibitor Bimiralisib (PQR309) in Relapsed, Refractory Lymphoma // HemaSphere. – 2021. – Vol. 5, № 11. – P. e656. https://doi.org/10.1097/HS9.0000000000000656.
48. Yang K., Tang X., Xu F. et al. PI3K/mTORC1/2 inhibitor PQR309 inhibits proliferation and induces apoptosis in human glioblastoma cells // Oncology Reports. – 2020. – Vol. 43, № 3. – 773–782. https://doi.org/10.3892/or.2020.7472.
49. Rozengurt E., Soares H. P., Sinnet-Smith J. Suppression of feedback loops mediated by pi3k/mtor induces multiple overactivation of compensatory pathways: An unintended consequence leading to drug resistance // Molecular Cancer Therapeutics. – 2014. – Vol. 13, № 11. – P. 2477–2488. https://doi.org/10.1158/1535-7163.MCT-14-0330.
50. Gremke N., Besong I., Stroh A. et al. Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs // Signal Transduction and Targeted Therapy. – 2025. – Vol. 10, № 1. – P. 92. https://doi.org/10.1038/s41392-025-02180-4.
51. Zhang B., Zhang Q., Xiao Z. et al. Design, synthesis and biological evaluation of substituted 2-(thiophen-2-yl)1,3,5-triazine derivatives as potential dual PI3Kα/mTOR inhibitors // Bioorganic Chemistry. – 2020. – Vol. 95. – 103525. https://doi.org/10.1016/j.bioorg.2019.103525.
52. Wellbrock C., Karasarides M., Marais R. The RAF proteins take centre stage // Nature Reviews Molecular Cell Biology. – 2004. – Vol. 5. – P. 875–885. https://doi.org/10.1038/nrm1498.
53. Davies H., Bignell G. R., Cox C. et al. Mutations of the BRAF gene in human cancer // Nature. – 2002. – Vol. 417. – P. 949–954. https://doi.org/10.1038/nature00766.
Review
For citations:
Chernov I.S., Popova E.A., Protas A.V., Molchanov O.E., Sharoyko V.V., Semenov K.N. Phosphoinositol-3-kinase (PI3K) inhibitors based on 1,3,5-triazine derivatives for targeted antitumor therapy. The Scientific Notes of the Pavlov University. 2025;32(3):42-52. (In Russ.) https://doi.org/10.24884/1607-4181-2025-32-3-42-52
Views:
56
Email this article 