Identificación de inhibidores de PI3Kα mediante diseño de farmacóforos y reposicionamiento farmacológico†

  1. Paolo Wong Chero 1
  2. Daniel Ramírez Lupuche 1
  3. Richard Zapata Dongo 1
  4. Brenda Moy Díaz 1
  5. Stefany Infante Varillas 1
  6. Juan Faya Castillo 1
  1. 1 Universidad de Piura, Facultad de Medicina Humana, Lima, Perú.
Revista:
Horizonte médico

ISSN: 2227-3530,  1727-558X

Ano de publicación: 2024

Título do exemplar: Julio-Septiembre

Volume: 24

Número: 3

Tipo: Artigo

DIALNET GOOGLE SCHOLAR lock_openDialnet editor

Outras publicacións en: Horizonte médico

Resumo

Objective: PI3K is one of the most frequently mutated proteins in cancer, resulting in changes to its functions in regulating metabolism, immunity, among others. Despite the identification of specific drugs targeting PI3K, significant resistance to these therapies has been observed. Therefore, the search for new inhibitors is crucial. This project proposes a strategy based on in silico computational tools for screening Food and Drug Administration (FDA)-approved drugs, aiming to evaluate their potential for drug repositioning. Materials and methods: This study obtained the sequence of PI3Kα from UniProt Knowledgebase and its three-dimensional structure from AlphaFold Protein Structure Database, which were then coupled with adenosine triphosphate (ATP) and its selective inhibitors: inavolisib, taselisib, CH5132799, alpelisib and ZSTK474. Drug-protein interaction analysis was performed using Protein-Ligand Interaction Profiler (PLIP) and its visualization was done in PyMOL. Based on this information, pharmacophores were generated as models for virtual screening using PHARMIT and the FDA-approved drug library (https://pharmit.csb.pitt.edu/search.html). Results: Key atomistic positions of drug-protein interactions were identified based on the selective PI3Kα inhibitors interaction, leading to the generation of nine pharmacophores. A virtual screening resulted in 22 drugs that met the proposed criteria, out of which 10 had binding energy values (kcal/mol) equal to or higher than the PI3Kα inhibitors. Subsequently, three drugs with potential use for drug repositioning were selected. Conclusions: This study proposes fostamatinib, pralatrexate and entecavir as possible candidates for drug repositioning. Additionally, the nine pharmacophores can be utilized in other drug databases for identifying new molecules and/or drugs with potential for drug repositioning. Further in silico and in vitro studies of the proposed drugs are recommended.

Referencias bibliográficas

  • Arafeh R, Samuels Y. PIK3CA in cancer: The past 30 years. Semin Cancer Biol [Internet]. 2019;59:36–49.
  • Astudillo-de la Vega H, Ruiz-García E, Martínez-Cedillo J, Ochoa-Carrillo FJ. El papel de la quimiorresistencia en los tumores sólidos. Gac Mex Oncol [Internet]. 2010;9(3):117–26.
  • Bae JY, Lee GE, Park H, Cho J, Kim J, Lee J, et al. Antiviral efficacy of pralatrexate against SARS-CoV-2. Biomol Ther (Seoul) [Internet]. 2021;29(3):268–72.
  • Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther [Internet]. 2006;319(3):998–1008.
  • Brüning A, Burger P, Gingelmaier A, Mylonas I. The HIV reverse transcriptase inhibitor tenofovir induces cell cycle arrest in human cancer cells. Invest New Drugs [Internet]. 2012;30(4):1389–95.
  • Bussel J, Arnold DM, Grossbard E, Mayer J, Treliński J, Homenda W, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebocontrolled trials. Am J Hematol [Internet]. 2018;93(7):921–30.
  • 21. Clark RA, Lee S, Qiao J, Chung DH. Preclinical evaluation of the anti-tumor activity of pralatrexate in high-risk neuroblastoma cells. Oncotarget [Internet]. 2020;11(32):3069–77
  • Clarke PA, Workman P. Phosphatidylinositide-3-kinase inhibitors: addressing questions of isoform selectivity and pharmacodynamic/ predictive biomarkers in early clinical trials. J Clin Oncol [Internet]. 2012;30(3):331–3.
  • Flinn IW, Bartlett NL, Blum KA, Ardeshna KM, LaCasce AS, Flowers CR, et al. A phase II trial to evaluate the efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Eur J Cancer [Internet]. 2016;54:11–7
  • Gharbi SI, Zvelebil MJ, Shuttleworth SJ, Hancox T, Saghir N, Timms JF, et al. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J [Internet]. 2007;404(1):15–21
  • Heffron TP, Heald RA, Ndubaku C, Wei B, Augistin M, Do S, et al. The rational design of selective benzoxazepin inhibitors of the α-isoform of phosphoinositide 3-Kinase culminating in the identification of ( S )-2-((2-(1-isopropyl-1 H -1,2,4-triazol-5-yl)-5,6-dihydrobenzo[ f ] imidazo[1,2- d ][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326). J Med Chem [Internet]. 2016;59(3):985–1002.
  • Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov [Internet]. 2005;4(12):988–1004.
  • Lourenço T, Vale N. Pharmacological efficacy of repurposing drugs in the treatment of prostate cancer. Int J Mol Sci [Internet]. 2023;24(4):4154.
  • Maheshwari S, Miller MS, O’Meally R, Cole RN, Amzel LM, Gabelli SB. Kinetic and structural analyses reveal residues in phosphoinositide 3-kinase α that are critical for catalysis and substrate recognition. J Biol Chem [Internet]. 2017;292(33):13541–50.
  • Marchi E, O’Connor OA. Safety and efficacy of pralatrexate in the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Ther Adv Hematol [Internet]. 2012;3(4):227–35.
  • Mishra R, Patel H, Alanazi S, Kilroy MK, Garrett JT. PI3K inhibitors in cancer: Clinical implications and adverse effects. Int J Mol Sci [Internet]. 2021;22(7):3464.
  • Park SR, Speranza G, Piekarz R, Wright JJ, Kinders RJ, Wang L, et al. A multi-histology trial of fostamatinib in patients with advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and pheochromocytomas. Cancer Chemother Pharmacol [Internet]. 2013;71(4):981–90.
  • Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov [Internet]. 2019;18(1):41–58.
  • Robinson DM, Scott LJ, Plosker GL. Entecavir: a review of its use in chronic hepatitis B. Drugs. 2006;66(12):1605–22.
  • Sherin DR, Manojkumar TK. Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach. Sci Rep [Internet]. 2021;11(1):16251.
  • Shinde A, Hardy SD, Kim D, Akhand SS, Jolly MK, Wang WH, et al. Spleen tyrosine kinase–mediated autophagy is required for epithelial– mesenchymal plasticity and metastasis in breast cancer. Cancer Res [Internet]. 2019;79(8):1831–43.
  • Sung YM, Xu X, Sun J, Mueller D, Sentissi K, Johnson P, et al. Tumor suppressor function of Syk in human MCF10A in vitro and normal mouse mammary epithelium in vivo. PLOS ONE [Internet]. 2009;4(10):e7445.
  • Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov [Internet]. 2021;20(10):741–69.
  • Vulpetti A, Bosotti R. Sequence and structural analysis of kinase ATP pocket residues. Il Farm [Internet]. 2004;59(10):759–65.
  • Wang Y, Kuramitsu Y, Baron B, Kitagawa T, Tokuda K, Akada J, et al. PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. Int J Oncol [Internet]. 2017;50(2):606–12.
  • Walker EH, Perisic O, Ried C, Stephens L, Williams RL. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature [Internet]. 1999;402(6759):313–20.
  • Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD, et al. Wortmannin inactivates phosphoinositide 3-Kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol [Internet]. 1996;16(4):1722–33.
  • Zhang Y, Kwok-Shing Ng P, Kucherlapati M, Chen F, Liu Y, Tsang YH, et al. A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell [Internet]. 2017;31(6):820-32
  • Zhang M, Jang H, Nussinov R. PI3K inhibitors: review and new strategies. Chem Sci [Internet]. 2020;11(23):5855–65.
  • Zhang M, Wang D, Liu H, Li H. Tenofovir decrease hepatocellular carcinoma recurrence in chronic hepatitis B patients after liver resection. Infect Agent Cancer [Internet]. 2018;13:19.
Fonte de datos: Dialnet