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Journals / Journal of the Turkish Chemical Society Section A: Chemistry / 2026 / Volume: 2026 Issue: 2

Investigating the Potential of Selective COX-2 Inhibitors as Multi-Targeted Agents Against KRAS Signaling

Dilan Konyar(DİCLE ÜNİVERSİTESİ, ECZACILIK FAKÜLTESİ, ECZACILIK MESLEK BİLİMLERİ BÖLÜMÜ, FARMASOTİK KİMYA ANABİLİM DALI)0000-0001-7275-1266
Hayati Okur(DİCLE ÜNİVERSİTESİ, ECZACILIK FAKÜLTESİ, ECZACILIK MESLEK BİLİMLERİ BÖLÜMÜ, FARMASOTİK KİMYA ANABİLİM DALI)0000-0001-6807-8208
Pages
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Publication Date
2026-07-25
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AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Thus, these drugs exhibiting increased docking scores have been validated as potential candidates for multi-targeted anticancer approaches that target mutations considered “drug-untargetable” by affecting RAS signaling networks.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:Oncogenic RAS (rat sarcoma virus) mutations cause approximately 30% of human malignancies and initiate tumorigenesis through an autocrine feedback mechanism involving the COX-2/PGE2 (cyclooxygenase-2/prostaglandin E2) pathway.
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Key Findings & Data:This study aims to assess the direct binding affinities and molecular interaction mechanisms of 17 distinct selective and semi-selective COX-2 inhibitors (Parecoxib, Cimicoxib, Celecoxib, Polmacoxib, Mavacoxib, Rofecoxib, etc.) with oncogenic KRAS.
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Conclusion & Impact:Thus, these drugs exhibiting increased docking scores have been validated as potential candidates for multi-targeted anticancer approaches that target mutations considered “drug-untargetable” by affecting RAS signaling networks.
🔬Design:Research Article
📍Scope:2020 Verileri
⚙️Variables:COX-2 inhibitors · KRAS · molecular docking

Abstract

Oncogenic RAS (rat sarcoma virus) mutations cause approximately 30% of human malignancies and initiate tumorigenesis through an autocrine feedback mechanism involving the COX-2/PGE2 (cyclooxygenase-2/prostaglandin E2) pathway. This study aims to assess the direct binding affinities and molecular interaction mechanisms of 17 distinct selective and semi-selective COX-2 inhibitors (Parecoxib, Cimicoxib, Celecoxib, Polmacoxib, Mavacoxib, Rofecoxib, etc.) with oncogenic KRAS. Molecular docking simulations were performed using the MOE 2020 (Molecular Operating Environment) program. The wild -type KRAS structure (PDB ID: 4OBE) (protein data bank), obtained by X-ray crystallography, was selected as the target protein. The docking scores (S), RMSD (root-mean-square deviation) values, and binding energies of the medicines were evaluated compared to the reference ligands guanosine diphosphate (GDP) (-6.73 kcal/mol) and guanosine triphosphate (GTP) (-6.87 kcal/mol). The docking data indicate that Parecoxib (-5.91 kcal/mol), Cimicoxib (-5.89 kcal/mol), and Celecoxib (-5.88 kcal/mol) demonstrate the highest binding affinity for KRAS oncoproteins. In line with findings from our previous study, the presence of sulfonamide/sulfonyl groups in the molecular structure and the interaction of aromatic rings with Switch I/II pockets were recognized as crucial factors for increased affinity. Additionally, Polmacoxib (-5.44 kcal/mol), which interacts with carbonic anhydrase (CA), has the potential to reduce systemic toxicity and inhibit oncogenic signaling within a more favorable therapeutic window due to its tissue-specific retention properties. Thus, these drugs exhibiting increased docking scores have been validated as potential candidates for multi-targeted anticancer approaches that target mutations considered “drug-untargetable” by affecting RAS signaling networks.

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Cite This Article

Konyar, D., Okur, H. (2026). Investigating the Potential of Selective COX-2 Inhibitors as Multi-Targeted Agents Against KRAS Signaling. Journal of the Turkish Chemical Society Section A: Chemistry, Volume: 2026 Issue: 2. https://doi.org/10.18596/jotcsa.1887482

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References (60)

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  32. Wang X, Wu J, Xiao A, Wang J, Tian J. Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs. Mol Cancer [Internet]. 2025 Sep 24;24(1):229. Available from:.
  33. Khalil NA, Ahmed EM, Tharwat T, Mahmoud Z. NSAIDs between past and present; a long journey towards an ideal COX-2 inhibitor lead. RSC Adv [Internet]. 2024;14(42):30647–61. Available from:.
  34. Singhal A, Li BT, O’Reilly EM. Targeting KRAS in cancer. Nat Med [Internet]. 2024 Apr 18;30(4):969–83. Available from:.
  35. Prior IA, Hood FE, Hartley JL. The frequency of ras mutations in cancer. Cancer Res [Internet]. 2020 Jul 15;80(14):2969–74. Available from:.
  36. Jayachandran P, Elliott A, Soni S, Battaglin F, Mittal P, Algaze S, et al. Pan-RAS inhibitors and polo-like kinase 1: Promising targets in colorectal cancer. Oncogene [Internet]. 2025 Aug 11;44(30):2565–73. Available from:.
  37. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov [Internet]. 2012 May 1;2(5):401–4. Available from:.
  38. Isermann T, Sers C, Der CJ, Papke B. KRAS inhibitors: Resistance drivers and combinatorial strategies. Trends in Cancer [Internet]. 2025 Feb;11(2):91–116. Available from:.
  39. Hsu AL, Ching TT, Wang DS, Song X, Rangnekar VM, Chen CS. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem [Internet]. 2000 Apr;275(15):11397–403. Available from:.
  40. Greenhough A, Smartt HJM, Moore AE, Roberts HR, Williams AC, Paraskeva C, et al. The COX-2/PGE2 pathway: Key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis [Internet]. 2009 Jan 9;30(3):377–86. Available from:.
  41. Pan Y, Jiang Y, Tan L, Ravoori MK, Gagea M, Kundra V, et al. Deletion of cyclooxygenase-2 inhibits K-ras-induced lung carcinogenesis. Oncotarget [Internet]. 2015 Nov 17;6(36):38816–26. Available from:.
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  43. Kim HT, Cha H, Hwang KY. Structural insight into the inhibition of carbonic anhydrase by the COX-2-selective inhibitor polmacoxib (CG100649). Biochem Biophys Res Commun [Internet]. 2016 Sep;478(1):1–6. Available from:.
  44. Martina SD, Vesta KS, Ripley TL. Etoricoxib: A highly selective COX-2 inhibitor. Ann Pharmacother [Internet]. 2005 May 1;39(5):854–62. Available from:.
  45. Sinha SD, Prasad TB, Konatham B, Sriramadasu SC, Karmakar A, Sharma AK, et al. Polmacoxib 2mg in patients with mild to moderate idiopathic osteoarthritis of hip/knee-a randomized, double-anonymous study. Pain Manag [Internet]. 2024 Sep 15;14(9):497–506. Available from:.
  46. Chegaev K, Lazzarato L, Tosco P, Cena C, Marini E, Rolando B, et al. NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties. J Med Chem [Internet]. 2007 Apr 1;50(7):1449–57. Available from:.
  47. Cheer SM, Goa KL. Parecoxib (Parecoxib sodium). Drugs [Internet]. 2001;61(8):1133–41. Available from:. 18. Bai G, Sun X, Dou Q, Li B, Qin K, Sun X, et al. Analgesic application of a novel non-steroidal anti-inflammatory drug imrecoxib after total knee arthroplasty: A prospective randomized controlled study. Perioper Med [Internet]. 2025 Jul 15;14(1):73. Available from:.
  48. Buzelato Carli I, Fielding L. Long-term firocoxib use in horses. J Vet Intern Med [Internet]. 2025 May 1;39(3):e70117. Available from:.
  49. Wilson SE, Carpenter JW, Gardhouse S, KuKanich B. Pharmacokinetics of mavacoxib in New Zealand White rabbits ( ). Am J Vet Res [Internet]. 2023 Apr 3;54(5):1–5. Available from:.
  50. Konyar D, Okur H, Arslan Z. Molecular docking studies of COX inhibitors on wild-type RAS. J Fac Pharm Ankara Univ [Internet]. 2022 Oct 22;46(1):23–34. Available from:.
  51. Wang Y, Kaiser CE, Frett B, Li H yu. Targeting mutant KRAS for anticancer therapeutics: A review of novel small molecule modulators. J Med Chem [Internet]. 2013 Jul 11;56(13):5219–30. Available from:.
  52. Hunter JC, Gurbani D, Ficarro SB, Carrasco MA, Lim SM, Choi HG, et al. In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. Proc Natl Acad Sci [Internet]. 2014 Jun 17;111(24):8895–900. Available from:.
  53. Śledź P, Caflisch A. Protein structure-based drug design: from docking to molecular dynamics. Curr Opin Struct Biol [Internet]. 2018 Feb;48:93–102. Available from:.
  54. Corbeil CR, Williams CI, Labute P. Variability in docking success rates due to dataset preparation. J Comput Aided Mol Des [Internet]. 2012 Jun 8;26(6):775–86. Available from:.
  55. Xiong GL, Ye WL, Shen C, Lu AP, Hou TJ, Cao DS. Improving structure-based virtual screening performance via learning from scoring function components. Brief Bioinform [Internet]. 2021 May 20;22(3):bbaa094. Available from:.
  56. Weinberg R. ras Oncogenes and the molecular mechanisms of carcinogenesis. Blood [Internet]. 1984 Dec 1;64(6):1143–5. Available from:.
  57. Milburn M V., Tong L, deVos AM, Brünger A, Yamaizumi Z, Nishimura S, et al. Molecular switch for signal transduction: Structural differences between active and inactive forms of protooncogenic ras proteins. Science (80- ) [Internet]. 1990 Feb 23;247(4945):939–45. Available from:.
  58. McCarthy MJ, Pagba C V., Prakash P, Naji AK, van der Hoeven D, Liang H, et al. Discovery of high-affinity noncovalent allosteric KRAS inhibitors that disrupt effector binding. ACS Omega [Internet]. 2019 Feb 28;4(2):2921–30. Available from:.
  59. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell [Internet]. 1998 May;93(5):705–16. Available from:.
  60. Seed MP, Brown JR, Freemantle CN, Papworth JL, Colville-Nash PR, Willis D, et al. The Inhibition of colon-26 Adenocarcinoma Development and Angiogenesis by Topical Diclofenac in 2.5% Hyaluronan1 | Cancer Research | American Association for Cancer Research. Cancer Res [Internet]. 1997;57(9):1625–9. Available from:.