Design and synthesis of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) as potent estrogen receptor alpha inhibitors: targeted treatment of hormone-dependent breast cancer cells

Design and synthesis of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) as potent estrogen receptor alpha inhibitors: targeted treatment of hormone-dependent breast cancer cells Full article

Journal

RSC Medicinal Chemistry
ISSN: 2632-8682

Output data

Year: 2024, Volume: 15, Number: 7, Pages: 2380-2399 Pages count : 20 DOI: 10.1039/d4md00153b

Authors

Volkova Yulia ¹ , Scherbakov Alexander ^2,3 , Dzichenka Yaraslau ⁴ , Komkov Alexander ¹ , Bogdanov Fedor ^2,5 , Salnikova Diana ^2,1 , Dmitrenok Andrey ¹ , Sachanka Antos ⁴ , Sorokin Danila ² , Zavarzin Igor ¹

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp, 119991 Moscow, Russia
2	Department of Experimental Tumor Biology, N. N. Blokhin National Medical Research Center of Oncology, 24 Kashirskoe shosse, 115522 Moscow, Russia
3	Gause Institute of New Antibiotics, 11 Bol'shaya Pirogovskaya ulitsa, 119021 Moscow, Russia
4	Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 5/2 Kuprevich Str, 220141, Minsk, Belarus
5	Faculty of Medicine, Moscow State University, 27-1 Lomonosovsky prosp, 119192, Moscow, Russia

Estrogen receptor alpha (ERα) is an important target for the discovery of new therapeutic drugs against hormone-dependent breast cancer. A series of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) were synthesized and biologically evaluated as potent ERα inhibitors. Pho-STPYRs showed cytotoxicity against breast cancer cells with IC50 values of 5.9 μM and higher. Pho-STPYRs 33 and 34 [IC50 (MCF7) = 6.5 and 5.9 μM, respectively] were found to block the expression of ERα, the main driver of breast cancer growth, and modulate the ERK, cyclin D1, and CDK4 pathways. Compound 34 showed selectivity, anti-estrogenic potency and high antiproliferative efficacy in combination with the AKT inhibitor. Molecular docking was used to more accurately define the binding mode of lead compounds 33 and 34 to ERα. The selectivity analysis showed that lead compounds 33 and 34 produce no effects on cytochromes P450, including CYP7A1, CYP7B1, CYP17A1, CYP19A1, and CYP21A2. In a word, Pho-STPYRs 33 and 34 are promising ERα inhibitors for the treatment of hormone-dependent breast cancer.

Volkova Y. , Scherbakov A. , Dzichenka Y. , Komkov A. , Bogdanov F. , Salnikova D. , Dmitrenok A. , Sachanka A. , Sorokin D. , Zavarzin I.
Design and synthesis of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) as potent estrogen receptor alpha inhibitors: targeted treatment of hormone-dependent breast cancer cells
RSC Medicinal Chemistry. 2024. V.15. N7. P.2380-2399. DOI: 10.1039/d4md00153b WOS Scopus OpenAlex

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