Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge stud...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2025.2468852 |
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| _version_ | 1850139599220768768 |
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| author | Hussam Albassam Omar Almutairi Majed Alnasser Faisal Altowairqi Faris Almutairi Saad Alobid |
| author_facet | Hussam Albassam Omar Almutairi Majed Alnasser Faisal Altowairqi Faris Almutairi Saad Alobid |
| author_sort | Hussam Albassam |
| collection | DOAJ |
| description | Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge study employed a structure-based virtual screening of ∼3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3Kα inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal cancer cell proliferation, with an IC50 of 12.14 µM, while maintaining high selectivity by minimising activity against other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019’s binding interactions with key amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3Kα dysregulation, offering promising new possibilities for effective CRC treatment. |
| format | Article |
| id | doaj-art-f7881c4a34b84fbda74cb1a98cda0fd5 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-f7881c4a34b84fbda74cb1a98cda0fd52025-08-20T02:30:13ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2468852Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapyHussam Albassam0Omar Almutairi1Majed Alnasser2Faisal Altowairqi3Faris Almutairi4Saad Alobid5Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaColorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge study employed a structure-based virtual screening of ∼3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3Kα inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal cancer cell proliferation, with an IC50 of 12.14 µM, while maintaining high selectivity by minimising activity against other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019’s binding interactions with key amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3Kα dysregulation, offering promising new possibilities for effective CRC treatment.https://www.tandfonline.com/doi/10.1080/14756366.2025.2468852Colorectal cancerPI3K signalling pathwayPI3Kα inhibitorcancer drug discoverystructure-based virtual screening |
| spellingShingle | Hussam Albassam Omar Almutairi Majed Alnasser Faisal Altowairqi Faris Almutairi Saad Alobid Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy Journal of Enzyme Inhibition and Medicinal Chemistry Colorectal cancer PI3K signalling pathway PI3Kα inhibitor cancer drug discovery structure-based virtual screening |
| title | Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy |
| title_full | Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy |
| title_fullStr | Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy |
| title_full_unstemmed | Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy |
| title_short | Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy |
| title_sort | discovery of a selective pi3kα inhibitor via structure based virtual screening for targeted colorectal cancer therapy |
| topic | Colorectal cancer PI3K signalling pathway PI3Kα inhibitor cancer drug discovery structure-based virtual screening |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2468852 |
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