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Volume 26
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10.3390/ijms262311404
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Article

Anti-Cancer Outcome of Glucocorticoid Receptor Transrepression by Synephrine Derivatives in Hematological Malignancies

by
Ekaterina M. Zhidkova
1,†,
Ekaterina D. Savina
1,†,
Daria V. Migaleva
1,
Olga A. Vlasova
1,
Timur T. Valiev
2,
Adel D. Enikeev
3,
Gennadii A. Badun
4,
Maria G. Chernysheva
4,
Svetlana A. Dodonova
5,
Alexey A. Kryukov
5,
Pavel A. Kusov
1,
Kirill V. Gordeev
6,
Ekaterina A. Yurchenko
7,
Andrey V. Matveev
8,
Marianna G. Yakubovskaya
1,9 and
Ekaterina A. Lesovaya
1,9,10,*
1
Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia
2
Department of Hemoblastosis Chemotherapy, Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia
3
Oncogene Regulation Department, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, Kashirskoe Shosse 24-15, Moscow 115478, Russia
4
Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskiye Gory 1, Moscow 119991, Russia
5
Department of Pathophysiology, Kursk State Medical University, Karl Marx St. 3, Kursk 305041, Russia
6
Laboratory of Biologically Active Nanostructures, Gamaleya Research Institute of Epidemiology and Microbiology, Gamalei St. 18, Moscow 123098, Russia
7
Laboratory for Biological Testing and the Mechanism of Action of Biologically Active Substances, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, 159 Prospect 100-Letiya Vladivostoka, Vladivostok 690022, Russia
8
Department of Biotechnology and Industrial Pharmacy, Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, 86 Vernadsky Prospekt, Moscow 119571, Russia
9
Institute of Medicine, Peoples’ Friendship University of Russia, Miklukho-Maklaya St. 6, Moscow 117198, Russia
10
Oncology Department, I.P. Pavlov Ryazan State Medical University, Ministry of Health of Russia, Ryazan 390026, Russia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(23), 11404; https://doi.org/10.3390/ijms262311404
Submission received: 22 October 2025 / Revised: 19 November 2025 / Accepted: 20 November 2025 / Published: 25 November 2025
Versions Notes

Abstract

Glucocorticoids (GCs) represent effective anti-cancer drugs for the treatment of hematological malignancies, but their clinical use is limited due to their multiple adverse effects. Selective glucocorticoid receptor agonists/modulators (SEGRAMs) modify glucocorticoid receptor (GR) function, shifting it towards therapeutically important transrepression and, therefore, could be safer alternative to GCs. Here we report on the biological activity of four novel glucocorticoid receptor (GR) ligands, derivatives of synephrine, a natural-origin molecule. We demonstrated the affinity of synephrine derivatives in silico and in vitro by molecular dynamics simulation and radioligand binding assay, correspondingly. Further, we tested the induction of apoptosis in cultured cells and cytotoxic effects in primary lymphoblasts from patients with acute lymphoblastic leukemia. Therapeutically important GR transrepression was evaluated by luciferase reporter assay and Q-PCR of transrepression marker genes, while GR transactivation associated with side effects was evaluated by Q-PCR analysis and by the level of GR phosphorylation at Ser211. Anti-cancer effects of the leader compound, 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2), were studied using a murine transplantable lymphoma P388 model. The potential of 10S-E2 to prevent the development of atrophic complication was evaluated using a murine model of glucocorticoid-induced osteoporosis. All studied synephrine derivatives demonstrated high GR affinity, with the IC50 value of the most active derivative 10S-E2 being 0.56 µM; the effects on GR function were cell-type-specific. The leader compound, 10S-E2, revealed SEGRAM properties in vitro and demonstrated anti-cancer effects in vivo, inhibiting tumor growth by more than 60%. Although the anti-cancer effect of 10S-E2 was less pronounced than that of the reference drug dexamethasone, non-atrophogenic properties of 10S-E2 make this molecule an attractive candidate for long-term GR-associated therapies.
Keywords: glucocorticoid; selective glucocorticoid receptor agonist/modulator; lymphoma; leukemia; transrepression; transactivation; osteoporosis; skin atrophy; primary lymphoblast; synephrine derivatives glucocorticoid; selective glucocorticoid receptor agonist/modulator; lymphoma; leukemia; transrepression; transactivation; osteoporosis; skin atrophy; primary lymphoblast; synephrine derivatives

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MDPI and ACS Style

Zhidkova, E.M.; Savina, E.D.; Migaleva, D.V.; Vlasova, O.A.; Valiev, T.T.; Enikeev, A.D.; Badun, G.A.; Chernysheva, M.G.; Dodonova, S.A.; Kryukov, A.A.; et al. Anti-Cancer Outcome of Glucocorticoid Receptor Transrepression by Synephrine Derivatives in Hematological Malignancies. Int. J. Mol. Sci. 2025, 26, 11404. https://doi.org/10.3390/ijms262311404

AMA Style

Zhidkova EM, Savina ED, Migaleva DV, Vlasova OA, Valiev TT, Enikeev AD, Badun GA, Chernysheva MG, Dodonova SA, Kryukov AA, et al. Anti-Cancer Outcome of Glucocorticoid Receptor Transrepression by Synephrine Derivatives in Hematological Malignancies. International Journal of Molecular Sciences. 2025; 26(23):11404. https://doi.org/10.3390/ijms262311404

Chicago/Turabian Style

Zhidkova, Ekaterina M., Ekaterina D. Savina, Daria V. Migaleva, Olga A. Vlasova, Timur T. Valiev, Adel D. Enikeev, Gennadii A. Badun, Maria G. Chernysheva, Svetlana A. Dodonova, Alexey A. Kryukov, and et al. 2025. "Anti-Cancer Outcome of Glucocorticoid Receptor Transrepression by Synephrine Derivatives in Hematological Malignancies" International Journal of Molecular Sciences 26, no. 23: 11404. https://doi.org/10.3390/ijms262311404

APA Style

Zhidkova, E. M., Savina, E. D., Migaleva, D. V., Vlasova, O. A., Valiev, T. T., Enikeev, A. D., Badun, G. A., Chernysheva, M. G., Dodonova, S. A., Kryukov, A. A., Kusov, P. A., Gordeev, K. V., Yurchenko, E. A., Matveev, A. V., Yakubovskaya, M. G., & Lesovaya, E. A. (2025). Anti-Cancer Outcome of Glucocorticoid Receptor Transrepression by Synephrine Derivatives in Hematological Malignancies. International Journal of Molecular Sciences, 26(23), 11404. https://doi.org/10.3390/ijms262311404

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