{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T04:08:32Z","timestamp":1774238912803,"version":"3.50.1"},"reference-count":71,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017638","name":"Ministry of Health of the Russian Federation","doi-asserted-by":"crossref","award":["ZUNI-2025-0004"],"award-info":[{"award-number":["ZUNI-2025-0004"]}],"id":[{"id":"10.13039\/501100017638","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ufa Institute of Chemistry UFRC RAS Kinetic, Spectral-Luminescent, and Theoretical Investigation of Key Intermediates in Chemical and Biochemical Oxidation Processes","award":["125020601626\u20139"],"award-info":[{"award-number":["125020601626\u20139"]}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"crossref","award":["#25-15-00086"],"award-info":[{"award-number":["#25-15-00086"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) is a well-known transcriptional regulator that mediates a broad spectrum of cellular responses to hypoxia, including angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. These activities can be achieved by upregulation of numerous genes, such as vascular endothelial growth factors, fibroblast growth factors, and platelet-derived growth factors, which are involved in the growth regulation of normal tissues and solid tumors. Notably, HIF-1\u03b1-mediated regulation of the solid tumor\u2019s microenvironment effectively modulates tumor sensitivity to anticancer therapies and thereby can contribute to disease progression. Methods: The study was performed on breast, lung and prostate cancer cell lines. Protein expression was examined by western blotting. Antitumor activity of 2-ANPC was measured by syngeneic 4T1 breast cancer mouse model. Results: We show here that a 2-aminopyrrole derivative (2-amino-1-benzamido-5-(2-(naphthalene-2-yl)-2-oxoethylidene)-4-oxo-4,5-dihydro-1-H-pyrrole-3-carboxamide\u20142-ANPC), previously shown as a potent microtubule-targeting agent, effectively downregulates HIF-1\u03b1 expression in a broad spectrum of cancer cell lines, including breast, lung, and prostate cancer. The downregulation of HIF-1\u03b1 expression in 2-ANPC-treated cancer cells was due to enhanced proteasome-mediated degradation, whereas the proteasome inhibitor MG-132 effectively reversed this downregulation. 2-ANPC\u2019s potency in downregulating HIF-1\u03b1 was also shown in vivo by using the 4T1 breast cancer syngraft model. Importantly, this 2-aminopyrrole derivative also downregulated the expression of vascular endothelial growth factor receptors 1 and 3 (VEGFR1 and 3) in 4T1 tumors, which correlated with decreased tumor weight and size. As expected, an increase in apoptotic (i.e., cleaved caspase-3-positive) cells was detected in 4T1 tumors treated with 2-aminopyrrole derivative. Lastly, using various computational tools, we identified four potential binding sites for 2-ANPC to interact with HIF-1\u03b1, HIF-1\u03b2, and the p300 complex. Conclusions: Collectively, we show here, for the first time, that HIF-1\u03b1 is a novel molecular target for the 2-aminopyrrole derivative (2-ANPC), thereby illustrating it as a potential scaffold for the development of potent chemotherapeutic agents with anti-angiogenic activity.<\/jats:p>","DOI":"10.3390\/cancers18010115","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T13:30:52Z","timestamp":1767187852000},"page":"115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypoxia-Inducible Factor-1\u03b1, a Novel Molecular Target for a 2-Aminopyrrole Derivative: Biological and Molecular Modeling Study"],"prefix":"10.3390","volume":"18","author":[{"given":"Svetlana S.","family":"Zykova","sequence":"first","affiliation":[{"name":"Perm State Pharmaceutical Academy, Perm 614990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4348-9141","authenticated-orcid":false,"given":"Tatyana","family":"Gessel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0293-2974","authenticated-orcid":false,"given":"Aigul","family":"Galembikova","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5344-9499","authenticated-orcid":false,"given":"Evgenii S.","family":"Mozhaitsev","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8481-0470","authenticated-orcid":false,"given":"Sophia S.","family":"Borisevich","sequence":"additional","affiliation":[{"name":"Ufa Institute of Chemistry, Ural Federal Research Center, Russian Academy of Sciences, Ufa 450054, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazim","family":"Igidov","sequence":"additional","affiliation":[{"name":"Perm State Pharmaceutical Academy, Perm 614990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6210-4660","authenticated-orcid":false,"given":"Emiliya S.","family":"Egorova","sequence":"additional","affiliation":[{"name":"Central Research Laboratory, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8213-427X","authenticated-orcid":false,"given":"Ekaterina","family":"Mikheeva","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Khromova","sequence":"additional","affiliation":[{"name":"Cytogenetics Laboratory, Carcinogenesis Institute, N.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2078-4274","authenticated-orcid":false,"given":"Pavel","family":"Kopnin","sequence":"additional","affiliation":[{"name":"Cytogenetics Laboratory, Carcinogenesis Institute, N.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0885-5994","authenticated-orcid":false,"given":"Alina","family":"Galyautdinova","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6312-2027","authenticated-orcid":false,"given":"Vladimir","family":"Luzhanin","sequence":"additional","affiliation":[{"name":"Perm State Pharmaceutical Academy, Perm 614990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3379-3065","authenticated-orcid":false,"given":"Maxim","family":"Shustov","sequence":"additional","affiliation":[{"name":"Perm State Pharmaceutical Academy, Perm 614990, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2415-1084","authenticated-orcid":false,"given":"Sergei","family":"Boichuk","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"},{"name":"Central Research Laboratory, Kazan State Medical University, Kazan 420012, Russia"},{"name":"Department of Radiotherapy and Radiology, Faculty of Surgery, Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0955-0674(00)00194-0","article-title":"HIF-1 and Mechanisms of Hypoxia Sensing","volume":"13","author":"Semenza","year":"2001","journal-title":"Curr. 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