{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T09:48:00Z","timestamp":1794649680692,"version":"4.9.1"},"reference-count":82,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004189","name":"Max-Planck-Gesellschaft","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100004189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Phosphoinositide 3-kinases (PI3Ks) are major regulators of cell growth, proliferation and signalling, constituting key therapeutic targets in cancer, inflammation, and other diseases. Individual class I PI3K isoforms control key cellular functions, imposing the need to generate isoform-specific inhibition for therapeutic intervention. Roginolisib is a selective PI3K\u03b4 inhibitor that shows promise for the treatment of cancer. Using a combination of X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, we describe the mechanism driving roginolisib\u2019s potent and isoform-selective inhibition of PI3K\u03b4. Roginolisib uniquely stabilises the catalytic C-terminal helix k\u03b112, locking the enzyme in an inactive conformation. This binding mode also results in more sustained inhibition of phosphatidylinositol 3,4,5-trisphosphate formation in tumour samples of CLL patients. Inhibition of PI3Ks by stabilization of helix k\u03b112 into an inactive conformation has not, to the best of our knowledge, been described before and may provide the basis for novel, more selective and effective pharmacological strategies.<\/jats:p>","DOI":"10.1038\/s41467-026-77424-0","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:02:40Z","timestamp":1791536560000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PI3K\u03b4 is selectively inhibited by roginolisib by stabilizing the C-terminal helix k\u03b112"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3511-6479","authenticated-orcid":false,"given":"Oscar","family":"Vadas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1712-5454","authenticated-orcid":false,"given":"Simon","family":"Tiede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Chaouki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2403-7129","authenticated-orcid":false,"given":"Laura","family":"Tesmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4892-5523","authenticated-orcid":false,"given":"Shanlin","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4022-7045","authenticated-orcid":false,"given":"R\u00e9my","family":"Visentin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1869-6945","authenticated-orcid":false,"given":"Ulrich","family":"Gr\u00e4dler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Augustin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiner","family":"Kiefersauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"G\u00f6\u00dfer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1849-6388","authenticated-orcid":false,"given":"Anne","family":"Quillet-Mary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lo\u00efc","family":"Ysebaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3173-4907","authenticated-orcid":false,"given":"Julie","family":"Guillermet-Guibert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4525-0081","authenticated-orcid":false,"given":"Lars","family":"van der Veen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1353-5867","authenticated-orcid":false,"given":"Giusy","family":"Di Conza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7768-746X","authenticated-orcid":false,"given":"Gerhard","family":"Hummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"77424_CR1","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/s41573-021-00209-1","volume":"20","author":"B Vanhaesebroeck","year":"2021","unstructured":"Vanhaesebroeck, B., Perry, M. W. D., Brown, J. R., Andr\u00e9, F. & Okkenhaug, K. PI3K inhibitors are finally coming of age. Nat. Rev. Drug Discov. 20, 741\u2013769, https:\/\/doi.org\/10.1038\/s41573-021-00209-1 (2021).","journal-title":"Nat. Rev. Drug Discov."},{"key":"77424_CR2","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1038\/s41580-019-0129-z","volume":"20","author":"B Bilanges","year":"2019","unstructured":"Bilanges, B., Posor, Y. & Vanhaesebroeck, B. PI3K isoforms in cell signalling and vesicle trafficking. Nat. Rev. Mol. Cell Bio 20, 515\u2013534 (2019).","journal-title":"Nat. Rev. Mol. Cell Bio"},{"key":"77424_CR3","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.coph.2015.05.016","volume":"23","author":"TA Yap","year":"2015","unstructured":"Yap, T. A., Bjerke, L., Clarke, P. A. & Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies. Curr. Opin. Pharm. 23, 98\u2013107 (2015).","journal-title":"Curr. Opin. Pharm."},{"key":"77424_CR4","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.tips.2023.06.002","volume":"44","author":"D Cirillo","year":"2023","unstructured":"Cirillo, D., Diceglie, M. & Nazar\u00e9, M. Isoform-selective targeting of PI3K: time to consider new opportunities? Trends Pharmacol. Sci. 44, 601\u2013621 (2023).","journal-title":"Trends Pharmacol. Sci."},{"key":"77424_CR5","doi-asserted-by":"publisher","first-page":"4330","DOI":"10.1073\/pnas.94.9.4330","volume":"94","author":"B Vanhaesebroeck","year":"1997","unstructured":"Vanhaesebroeck, B. et al. p110, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl. Acad. Sci. 94, 4330\u20134335 (1997).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"77424_CR6","doi-asserted-by":"publisher","first-page":"19236","DOI":"10.1074\/jbc.272.31.19236","volume":"272","author":"D Chantry","year":"1997","unstructured":"Chantry, D. et al. p110\u03b4, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes*. J. Biol. Chem. 272, 19236\u201319241 (1997).","journal-title":"J. Biol. Chem."},{"key":"77424_CR7","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/nri1056","volume":"3","author":"K Okkenhaug","year":"2003","unstructured":"Okkenhaug, K. & Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol. 3, 317\u2013330 (2003).","journal-title":"Nat. Rev. Immunol."},{"key":"77424_CR8","doi-asserted-by":"publisher","first-page":"105900","DOI":"10.1016\/j.phrs.2021.105900","volume":"173","author":"D Meng","year":"2021","unstructured":"Meng, D. et al. Development of PI3K inhibitors: advances in clinical trials and new strategies (Review). Pharmacol. Res. 173, 105900 (2021).","journal-title":"Pharmacol. Res."},{"key":"77424_CR9","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1517\/21678707.2014.978858","volume":"3","author":"Q Yang","year":"2014","unstructured":"Yang, Q., Modi, P., Ramanathan, S., Qu\u00e9va, C. & Gandhi, V. Idelalisib for the treatment of B-cell malignancies. Expert Opin. Orphan D. 3, 109\u2013123 (2014).","journal-title":"Expert Opin. Orphan D."},{"key":"77424_CR10","doi-asserted-by":"publisher","unstructured":"Richardson, N. C., Kasamon, Y., Pazdur, R. & Gormley, N. The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint. Lancet Oncol. https:\/\/doi.org\/10.1016\/s1470-2045(22)00200-5 (2022).","DOI":"10.1016\/s1470-2045(22)00200-5"},{"key":"77424_CR11","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/psp4.12749","volume":"11","author":"K Gadkar","year":"2021","unstructured":"Gadkar, K. et al. Quantitative systems pharmacology model-based investigation of Adverse Gastrointestinal Events Associated with Prolonged Treatment with PI3-Kinase (PI3K) Inhibitors. Cpt Pharmacomet. Syst. Pharm. 11, 616\u2013627, https:\/\/doi.org\/10.1002\/psp4.12749 (2021).","journal-title":"Cpt Pharmacomet. Syst. Pharm."},{"key":"77424_CR12","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1177\/10915818231200419","volume":"42","author":"L Veen","year":"2023","unstructured":"Veen, L., van der, Schmitt, M., Deken, M. A. & Lahn, M. Non-clinical toxicology evaluation of the novel non-ATP competitive oral PI3 kinase delta inhibitor roginolisib. Int. J. Toxicol. 42, 515\u2013534, https:\/\/doi.org\/10.1177\/10915818231200419 (2023).","journal-title":"Int. J. Toxicol."},{"key":"77424_CR13","doi-asserted-by":"publisher","first-page":"2432","DOI":"10.1158\/2159-8290.CD-23-0396","volume":"13","author":"L Buckbinder","year":"2023","unstructured":"Buckbinder, L. et al. STX-478, a mutant-selective, allosteric PI3Ka inhibitor spares metabolic dysfunction and improves therapeutic response in PI3Ka-mutant xenografts. Cancer Discov. 13, 2432\u20132447 (2023).","journal-title":"Cancer Discov."},{"key":"77424_CR14","doi-asserted-by":"publisher","first-page":"re2","DOI":"10.1126\/scisignal.2002165","volume":"4","author":"O Vadas","year":"2011","unstructured":"Vadas, O., Burke, J. E., Zhang, X., Berndt, A. & Williams, R. L. Structural basis for activation and inhibition of class I phosphoinositide 3-kinases. Sci. Signal. 4, re2 (2011).","journal-title":"Sci. Signal."},{"key":"77424_CR15","first-page":"1127","volume":"19","author":"JE Burke","year":"2011","unstructured":"Burke, J. E. et al. Dynamics of the phosphoinositide 3-kinase p110\u03b4 interaction with p85\u03b1 and membranes reveals aspects of regulation distinct from p110\u03b1. Struct. Lond. Engl. 1993 19, 1127\u20131137 (2011).","journal-title":"Struct. Lond. Engl. 1993"},{"key":"77424_CR16","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.molcel.2018.08.005","volume":"71","author":"JE Burke","year":"2018","unstructured":"Burke, J. E. Structural basis for regulation of phosphoinositide kinases and their involvement in human disease. Mol. Cell 71, 653\u2013673 (2018).","journal-title":"Mol. Cell"},{"key":"77424_CR17","doi-asserted-by":"publisher","first-page":"12256","DOI":"10.1074\/jbc.M117.789263","volume":"292","author":"BD Siempelkamp","year":"2017","unstructured":"Siempelkamp, B. D., Rathinaswamy, M. K., Jenkins, M. L. & Burke, J. E. Molecular mechanism of activation of class IA phosphoinositide 3-kinases (PI3Ks) by membrane-localized HRas. J. Biol. Chem. 292, 12256\u201312266 (2017).","journal-title":"J. Biol. Chem."},{"key":"77424_CR18","doi-asserted-by":"crossref","unstructured":"Giacomo, A. M. D. et al. 192P Safety and clinical activity of IOA-244: A highly selective phosphoinositide 3-kinase inhibitor delta (PI3K\u03b4), in a phase I first-in-human (FIH) study. Immuno-Oncol. Technol. 16, (2022).","DOI":"10.1016\/j.iotech.2022.100304"},{"key":"77424_CR19","doi-asserted-by":"publisher","unstructured":"Johnson, Z. et al. IOA-244 is a non-ATP-competitive, highly selective, tolerable phosphoinositide 3-kinase delta inhibitor that targets solid tumors and breaks immune tolerance. Cancer Res. Commun. (2023) https:\/\/doi.org\/10.1158\/2767-9764.crc-22-0477.","DOI":"10.1158\/2767-9764.crc-22-0477"},{"key":"77424_CR20","doi-asserted-by":"publisher","first-page":"3180","DOI":"10.1021\/ci200319e","volume":"51","author":"B Kuhn","year":"2011","unstructured":"Kuhn, B., Fuchs, J. E., Reutlinger, M., Stahl, M. & Taylor, N. R. Rationalizing tight ligand binding through cooperative interaction networks. J. Chem. Inf. Model. 51, 3180\u20133198 (2011).","journal-title":"J. Chem. Inf. Model."},{"key":"77424_CR21","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/nchembio.293","volume":"6","author":"A Berndt","year":"2010","unstructured":"Berndt, A. et al. The p110\u03b4 structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat. Chem. Biol. 6, 117 (2010).","journal-title":"Nat. Chem. Biol."},{"key":"77424_CR22","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1038\/372746a0","volume":"372","author":"SR Hubbard","year":"1994","unstructured":"Hubbard, S. R., Wei, L., Ellis, L. & Hendrickson, W. A. Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature 372, 746\u2013754 (1994).","journal-title":"Nature"},{"key":"77424_CR23","doi-asserted-by":"publisher","first-page":"5572","DOI":"10.1093\/emboj\/16.18.5572","volume":"16","author":"SR Hubbard","year":"1997","unstructured":"Hubbard, S. R. Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J. 16, 5572\u20135581 (1997).","journal-title":"EMBO J."},{"key":"77424_CR24","doi-asserted-by":"publisher","first-page":"3889","DOI":"10.1021\/jm400072p","volume":"56","author":"Y-H Peng","year":"2013","unstructured":"Peng, Y.-H. et al. Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. J. Med. Chem. 56, 3889\u20133903 (2013).","journal-title":"J. Med. Chem."},{"key":"77424_CR25","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.1021\/jm901443h","volume":"53","author":"F Zuccotto","year":"2010","unstructured":"Zuccotto, F., Ardini, E., Casale, E. & Angiolini, M. Through the \u201cgatekeeper door\u201d: exploiting the active kinase conformation. J. Med. Chem. 53, 2681\u20132694 (2010).","journal-title":"J. Med. Chem."},{"key":"77424_CR26","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1021\/cb500696t","volume":"10","author":"PM-U Ung","year":"2015","unstructured":"Ung, P. M.-U. & Schlessinger, A. DFGmodel: predicting protein kinase structures in inactive states for structure-based discovery of type-II inhibitors. ACS Chem. Biol. 10, 269\u2013278 (2015).","journal-title":"ACS Chem. Biol."},{"key":"77424_CR27","doi-asserted-by":"publisher","first-page":"3097","DOI":"10.1158\/1535-7163.MCT-16-0403","volume":"15","author":"JCM Uitdehaag","year":"2016","unstructured":"Uitdehaag, J. C. M. et al. Cell panel profiling reveals conserved therapeutic clusters and differentiates the mechanism of action of different PI3K\/mTOR, aurora kinase and EZH2 inhibitors. Mol. Cancer Ther. 15, 3097\u20133109 (2016).","journal-title":"Mol. Cancer Ther."},{"key":"77424_CR28","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","volume":"596","author":"J Jumper","year":"2021","unstructured":"Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583\u2013589 (2021).","journal-title":"Nature"},{"key":"77424_CR29","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.molcel.2011.01.026","volume":"41","author":"X Zhang","year":"2011","unstructured":"Zhang, X. et al. Structure of lipid kinase p110\u03b2\/p85\u03b2 elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol. Cell 41, 567\u2013578 (2011).","journal-title":"Mol. Cell"},{"key":"77424_CR30","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/46319","volume":"402","author":"EH Walker","year":"1999","unstructured":"Walker, E. H., Perisic, O., Ried, C., Stephens, L. & Williams, R. L. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402, 313\u2013320 (1999).","journal-title":"Nature"},{"key":"77424_CR31","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1126\/science.1184429","volume":"327","author":"S Miller","year":"2010","unstructured":"Miller, S. et al. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327, 1638\u20131642 (2010).","journal-title":"Science"},{"key":"77424_CR32","doi-asserted-by":"publisher","first-page":"18862","DOI":"10.1073\/pnas.1304801110","volume":"110","author":"O Vadas","year":"2013","unstructured":"Vadas, O. et al. Molecular determinants of PI3K\u03b3-mediated activation downstream of G-protein\u2013coupled receptors (GPCRs). Proc. Natl. Acad. Sci. USA 110, 18862\u201318867 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"77424_CR33","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/s41594-022-00730-w","volume":"29","author":"W-T Lo","year":"2022","unstructured":"Lo, W.-T. et al. Structural basis of phosphatidylinositol 3-kinase C2\u03b1 function. Nat. Struct. Mol. Biol. 29, 218\u2013228 (2022).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"77424_CR34","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1007\/978-1-0716-1197-5_22","volume":"2263","author":"JTB Stariha","year":"2021","unstructured":"Stariha, J. T. B., Hoffmann, R. M., Hamelin, D. J. & Burke, J. E. Protein-ligand interactions, methods and applications. Methods Mol. Biol. 2263, 465\u2013485 (2021).","journal-title":"Methods Mol. Biol."},{"key":"77424_CR35","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/S1097-2765(05)00089-4","volume":"6","author":"EH Walker","year":"2000","unstructured":"Walker, E. H. et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell 6, 909\u2013919 (2000).","journal-title":"Mol. Cell"},{"key":"77424_CR36","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/S0022-2275(20)39471-2","volume":"12","author":"EL GOTTFRIED","year":"1971","unstructured":"GOTTFRIED, E. L. Lipid patterns in human leukocytes maintained in long-term culture. J. Lipid Res. 12, 531\u2013537 (1971).","journal-title":"J. Lipid Res."},{"key":"77424_CR37","doi-asserted-by":"publisher","first-page":"4179","DOI":"10.1182\/blood-2023-180073","volume":"142","author":"BK Sasi","year":"2023","unstructured":"Sasi, B. K. et al. Novel Pi3k\u03b4 inhibitor roginolisib synergizes with the Bcl-2 inhibitor venetoclax in hematological malignancies. Blood 142, 4179 (2023).","journal-title":"Blood"},{"key":"77424_CR38","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.chembiol.2005.04.011","volume":"12","author":"ZA Knight","year":"2005","unstructured":"Knight, Z. A. & Shokat, K. M. Features of selective kinase inhibitors. Chem. Biol. 12, 621\u2013637 (2005).","journal-title":"Chem. Biol."},{"key":"77424_CR39","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1016\/j.bcp.2008.12.022","volume":"77","author":"LO Kirkland","year":"2009","unstructured":"Kirkland, L. O. & McInnes, C. Non-ATP competitive protein kinase inhibitors as anti-tumor therapeutics. Biochem Pharm. 77, 1561\u20131571 (2009).","journal-title":"Biochem Pharm."},{"key":"77424_CR40","doi-asserted-by":"publisher","first-page":"20677","DOI":"10.1074\/jbc.M110.213736","volume":"286","author":"S Eathiraj","year":"2011","unstructured":"Eathiraj, S. et al. A novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited kinases discovery of ATP-independent inhibitors of fibroblast growth factor receptor. J. Biol. Chem. 286, 20677\u201320687 (2011).","journal-title":"J. Biol. Chem."},{"key":"77424_CR41","doi-asserted-by":"publisher","first-page":"2804","DOI":"10.2174\/092986710791859333","volume":"17","author":"L Garuti","year":"2010","unstructured":"Garuti, L., Roberti, M. & Bottegoni, G. Non-ATP competitive protein kinase inhibitors. Curr. Med Chem. 17, 2804\u20132821 (2010).","journal-title":"Curr. Med Chem."},{"key":"77424_CR42","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1124\/mol.114.095489","volume":"87","author":"D Fabbro","year":"2015","unstructured":"Fabbro, D. 25 years of small molecular weight kinase inhibitors: potentials and limitations. Mol. Pharm. 87, 766\u2013775 (2015).","journal-title":"Mol. Pharm."},{"key":"77424_CR43","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/s41586-023-05972-2","volume":"618","author":"GQ Gong","year":"2023","unstructured":"Gong, G. Q. et al. A small-molecule PI3K\u03b1 activator for cardioprotection and neuroregeneration. Nature 618, 159\u2013168 (2023).","journal-title":"Nature"},{"key":"77424_CR44","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1074\/jbc.M109263200","volume":"277","author":"YV Budovskaya","year":"2002","unstructured":"Budovskaya, Y. V., Hama, H., DeWald, D. B. & Herman, P. K. The C-terminus of the Vps34p phosphoinositide 3-kinase is necessary and sufficient for the interaction with the Vps15p protein kinase*. J. Biol. Chem. 277, 287\u2013294 (2002).","journal-title":"J. Biol. Chem."},{"key":"77424_CR45","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.64691","volume":"10","author":"MK Rathinaswamy","year":"2021","unstructured":"Rathinaswamy, M. K. et al. Disease-related mutations in PI3K\u03b3 disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors. Elife 10, e64691 (2021).","journal-title":"Elife"},{"key":"77424_CR46","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1093\/emboj\/18.5.1292","volume":"18","author":"B Vanhaesebroeck","year":"1999","unstructured":"Vanhaesebroeck, B. et al. Autophosphorylation of p110\u03b4 phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo. Embo J. 18, 1292\u20131302 (1999).","journal-title":"Embo J."},{"key":"77424_CR47","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1021\/jm401642q","volume":"57","author":"V Certal","year":"2014","unstructured":"Certal, V. et al. Discovery and Optimization of pyrimidone indoline amide PI3K\u03b2 inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers. J. Med. Chem. 57, 903\u2013920 (2014).","journal-title":"J. Med. Chem."},{"key":"77424_CR48","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/s41589-018-0215-0","volume":"15","author":"G Gangadhara","year":"2019","unstructured":"Gangadhara, G. et al. A class of highly selective inhibitors bind to an active state of PI3K\u03b3. Nat. Chem. Biol. 15, 348\u2013357 (2019).","journal-title":"Nat. Chem. Biol."},{"key":"77424_CR49","unstructured":"Giacomo, D., Simonelli, M., Losurdo, A. & Michele, M. The conformation-selective PI3K\u03b4 inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human trial. Nat. Commun. NCOMMS-25-88822B,"},{"key":"77424_CR50","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1038\/s41375-022-01595-0","volume":"36","author":"MK Mamidi","year":"2022","unstructured":"Mamidi, M. K. et al. Idelalisib activates AKT via increased recruitment of PI3K\u03b4\/PI3K\u03b2 to BCR signalosome while reducing PDK1 in post-therapy CLL cells. Leukemia 36, 1806\u20131817 (2022).","journal-title":"Leukemia"},{"key":"77424_CR51","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1107\/S0021889800008049","volume":"33","author":"R Kiefersauer","year":"2000","unstructured":"Kiefersauer, R. et al. A novel free-mounting system for protein crystals: transformation and improvement of diffraction power by accurately controlled humidity changes. J. Appl. Crystallogr. 33, 1223\u20131230 (2000).","journal-title":"J. Appl. Crystallogr."},{"key":"77424_CR52","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1107\/S0907444911007773","volume":"67","author":"C Vonrhein","year":"2011","unstructured":"Vonrhein, C. et al. Data processing and analysis with the autoPROC toolbox. Acta Crystallogr. Sect. D: Biol. Crystallogr. 67, 293\u2013302 (2011).","journal-title":"Acta Crystallogr. Sect. D: Biol. Crystallogr."},{"key":"77424_CR53","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1107\/S0907444909047337","volume":"66","author":"WXDS Kabsch","year":"2010","unstructured":"Kabsch, W. X. D. S. Acta Crystallogr. D. Biol. Crystallogr. 66, 125\u2013132 (2010).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"77424_CR54","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1107\/S0907444913000061","volume":"69","author":"PR Evans","year":"2013","unstructured":"Evans, P. R. & Murshudov, G. N. How good are my data and what is the resolution? Acta Crystallogr. D. Biol. Crystallogr. 69, 1204\u20131214 (2013).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"77424_CR55","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","volume":"40","author":"AJ McCoy","year":"2007","unstructured":"McCoy, A. J. et al. Phaser crystallographic software. J. Appl Crystallogr. 40, 658\u2013674 (2007).","journal-title":"J. Appl Crystallogr."},{"key":"77424_CR56","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1107\/S0907444904019158","volume":"60","author":"P Emsley","year":"2004","unstructured":"Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D. Biol. Crystallogr. 60, 2126\u20132132 (2004).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"77424_CR57","doi-asserted-by":"publisher","first-page":"8439","DOI":"10.1074\/jbc.M114.634683","volume":"290","author":"JR Somoza","year":"2015","unstructured":"Somoza, J. R. et al. Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase \u03b4*. J. Biol. Chem. 290, 8439\u20138446 (2015).","journal-title":"J. Biol. Chem."},{"key":"77424_CR58","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","volume":"234","author":"A \u0160ali","year":"1993","unstructured":"\u0160ali, A. & Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779\u2013815 (1993).","journal-title":"J. Mol. Biol."},{"key":"77424_CR59","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1002\/j.1460-2075.1995.tb07082.x","volume":"14","author":"RM Xu","year":"1995","unstructured":"Xu, R. M., Carmel, G., Sweet, R. M., Kuret, J. & Cheng, X. Crystal structure of casein kinase-1, a phosphate-directed protein kinase. EMBO J. 14, 1015\u20131023 (1995).","journal-title":"EMBO J."},{"key":"77424_CR60","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","volume":"1","author":"MJ Abraham","year":"2015","unstructured":"Abraham, M. J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1, 19\u201325 (2015).","journal-title":"SoftwareX"},{"key":"77424_CR61","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1002\/jcc.10262","volume":"24","author":"KL Meagher","year":"2003","unstructured":"Meagher, K. L., Redman, L. T. & Carlson, H. A. Development of polyphosphate parameters for use with the AMBER force field. J. Comput. Chem. 24, 1016\u20131025 (2003).","journal-title":"J. Comput. Chem."},{"key":"77424_CR62","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1002\/prot.21123","volume":"65","author":"V Hornak","year":"2006","unstructured":"Hornak, V. et al. Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins: Struct. Funct. Bioinform. 65, 712\u2013725 (2006).","journal-title":"Proteins: Struct. Funct. Bioinform."},{"key":"77424_CR63","doi-asserted-by":"publisher","first-page":"9004","DOI":"10.1021\/jp901540t","volume":"113","author":"RB Best","year":"2009","unstructured":"Best, R. B. & Hummer, G. Optimized Molecular Dynamics Force Fields Applied to the Helix\u2212Coil Transition of Polypeptides. J. Phys. Chem. B 113, 9004\u20139015 (2009).","journal-title":"J. Phys. Chem. B"},{"key":"77424_CR64","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.1002\/prot.22711","volume":"78","author":"K Lindorff-Larsen","year":"2010","unstructured":"Lindorff-Larsen, K. et al. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins: Struct., Funct. Bioinform 78, 1950\u20131958 (2010).","journal-title":"Proteins: Struct., Funct. Bioinform"},{"key":"77424_CR65","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/nmeth.4067","volume":"14","author":"J Huang","year":"2017","unstructured":"Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71\u201373 (2017).","journal-title":"Nat. Methods"},{"key":"77424_CR66","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","volume":"25","author":"J Wang","year":"2004","unstructured":"Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A. & Case, D. A. Development and testing of a general amber force field. J. Comput. Chem. 25, 1157\u20131174 (2004).","journal-title":"J. Comput. Chem."},{"key":"77424_CR67","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/jcc.20945","volume":"29","author":"S Jo","year":"2008","unstructured":"Jo, S., Kim, T., Iyer, V. G. & Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859\u20131865 (2008).","journal-title":"J. Comput. Chem."},{"key":"77424_CR68","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1021\/acs.jctc.5b00935","volume":"12","author":"J Lee","year":"2016","unstructured":"Lee, J. et al. CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM Simulations Using the CHARMM36 Additive Force Field. J. Chem. Theory Comput. 12, 405\u2013413 (2016).","journal-title":"J. Chem. Theory Comput."},{"key":"77424_CR69","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","volume":"79","author":"WL Jorgensen","year":"1983","unstructured":"Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926\u2013935 (1983).","journal-title":"J. Chem. Phys."},{"key":"77424_CR70","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","volume":"98","author":"T Darden","year":"1993","unstructured":"Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: An N \u22c5log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089\u201310092 (1993).","journal-title":"J. Chem. Phys."},{"key":"77424_CR71","doi-asserted-by":"publisher","first-page":"3684","DOI":"10.1063\/1.448118","volume":"81","author":"HJC Berendsen","year":"1984","unstructured":"Berendsen, H. J. C. et al. Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, 3684\u20133690 (1984).","journal-title":"J. Chem. Phys."},{"key":"77424_CR72","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1063\/1.447334","volume":"81","author":"S Nos\u00e9","year":"1984","unstructured":"Nos\u00e9, S. A unified formulation of the constant temperature molecular dynamics methods. J. Chem. Phys. 81, 511\u2013519 (1984).","journal-title":"J. Chem. Phys."},{"key":"77424_CR73","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","volume":"31","author":"WG Hoover","year":"1985","unstructured":"Hoover, W. G. Canonical dynamics: equilibrium phase-space distributions. Phys. Rev. A 31, 1695\u20131697 (1985).","journal-title":"Phys. Rev. A"},{"key":"77424_CR74","doi-asserted-by":"publisher","first-page":"7182","DOI":"10.1063\/1.328693","volume":"52","author":"M Parrinello","year":"1981","unstructured":"Parrinello, M. & Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys. 52, 7182\u20137190 (1981).","journal-title":"J. Appl. Phys."},{"key":"77424_CR75","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1021\/acs.jctc.5b00209","volume":"11,","author":"TA Wassenaar","year":"2015","unstructured":"Wassenaar, T. A., Ingo\u0301lfsson, H. I., B\u00f6ckmann, R. A., Tieleman, D. P. & Marrink, S. J. Computational lipidomics with insane: a versatile tool for generating custom membranes for molecular simulations. J. Chem. Theory Comput. 11,, 2144\u20132155 (2015).","journal-title":"J. Chem. Theory Comput."},{"key":"77424_CR76","doi-asserted-by":"publisher","first-page":"6472","DOI":"10.1021\/acs.jctc.1c00295","volume":"17","author":"ON Vickery","year":"2021","unstructured":"Vickery, O. N. & Stansfeld, P. J. CG2AT2: an enhanced fragment-based approach for serial multi-scale molecular dynamics simulations. J. Chem. Theory Comput. 17, 6472\u20136482 (2021).","journal-title":"J. Chem. Theory Comput."},{"key":"77424_CR77","doi-asserted-by":"publisher","first-page":"014101","DOI":"10.1063\/1.2408420","volume":"126","author":"G Bussi","year":"2007","unstructured":"Bussi, G., Donadio, D. & Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007).","journal-title":"J. Chem. Phys."},{"key":"77424_CR78","doi-asserted-by":"publisher","first-page":"8577","DOI":"10.1063\/1.470117","volume":"103","author":"U Essmann","year":"1995","unstructured":"Essmann, U. et al. A smooth particle mesh Ewald method. J. Chem. Phys. 103, 8577\u20138593 (1995).","journal-title":"J. Chem. Phys."},{"key":"77424_CR79","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","volume":"18","author":"B Hess","year":"1997","unstructured":"Hess, B., Bekker, H., Berendsen, H. J. C. & Fraaije, J. G. E. M. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463\u20131472 (1997).","journal-title":"J. Comput. Chem."},{"key":"77424_CR80","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1002\/jcc.21787","volume":"32","author":"N Michaud-Agrawal","year":"2011","unstructured":"Michaud-Agrawal, N., Denning, E. J., Woolf, T. B. & Beckstein, O. MDAnalysis: a toolkit for the analysis of molecular dynamics simulations. J. Comput. Chem. 32, 2319\u20132327 (2011).","journal-title":"J. Comput. Chem."},{"key":"77424_CR81","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/nmeth.1564","volume":"8","author":"J Clark","year":"2011","unstructured":"Clark, J. et al. Quantification of PtdInsP3 molecular species in cells and tissues by mass spectrometry. Nat. Methods 8, 267\u2013272 (2011).","journal-title":"Nat. Methods"},{"key":"77424_CR82","doi-asserted-by":"publisher","unstructured":"Thibault, B. et al. Pancreatic cancer intrinsic PI3K\u03b1 activity accelerates metastasis and rewires macrophage component. EMBO Mol. Med. e13502 (2021) https:\/\/doi.org\/10.15252\/emmm.202013502.","DOI":"10.15252\/emmm.202013502"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-77424-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-77424-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-77424-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:02:43Z","timestamp":1791536563000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-77424-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":82,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["77424"],"URL":"https:\/\/doi.org\/10.1038\/s41467-026-77424-0","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"assertion":[{"value":"6 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"L.V.V. and G.D.C. are employees of the study Sponsor (iOnctura) and hold stock options. U.G. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. M.A., R.K. and C.G. are employees of Proteros biostructures GmbH, Munich, Germany. The remaining authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"10220"}}