Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents

Tomasz M. Wróbel; Oksana Rogova; Katyayani Sharma; Maria Natalia Rojas Velazquez; Amit V. Pandey; Flemming Steen Jørgensen; Frederic S. Arendrup; Kasper L. Andersen; Fredrik Björkling

doi:10.3390/biom12020165

Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents

Tomasz M. Wróbel^*, Oksana Rogova, Katyayani Sharma, Maria Natalia Rojas Velazquez, Amit V. Pandey, Flemming Steen Jørgensen, Frederic S. Arendrup, Kasper L. Andersen, Fredrik Björkling

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

9 Citationer (Scopus)

24 Downloads (Pure)

Abstract

Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC₅₀ 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure–activity relationship of this novel non-steroidal compound class.

Originalsprog	Engelsk
Artikelnummer	165
Tidsskrift	Biomolecules
Vol/bind	12
Udgave nummer	2
ISSN	2218-273X
DOI	https://doi.org/10.3390/biom12020165
Status	Udgivet - 2022

Bibliografisk note

Funding Information:
Funding: This research was funded by the Narodowe Centrum Nauki grant Sonata 16 2020/39/D/NZ7/ 00572 (T.M.W.). K.S. and M.N.R.V. are funded by Swiss Government Excellence Scholarships, Grant numbers 2019.0385 and 2020.0557.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Adgang til dokumentet

10.3390/biom12020165Licens: CC BY

FulltextForlagets udgivne version, 5,23 MBLicens: CC BY

Citationsformater

Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents. / Wróbel, Tomasz M.; Rogova, Oksana; Sharma, Katyayani; Velazquez, Maria Natalia Rojas; Pandey, Amit V.; Jørgensen, Flemming Steen ; Arendrup, Frederic S.; Andersen, Kasper L.; Björkling, Fredrik.

I: Biomolecules, Bind 12, Nr. 2, 165, 2022.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Wróbel, Tomasz M. ; Rogova, Oksana ; Sharma, Katyayani ; Velazquez, Maria Natalia Rojas ; Pandey, Amit V. ; Jørgensen, Flemming Steen ; Arendrup, Frederic S. ; Andersen, Kasper L. ; Björkling, Fredrik. / Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents. I: Biomolecules. 2022 ; Bind 12, Nr. 2.

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title = "Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents",

abstract = "Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC50 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure–activity relationship of this novel non-steroidal compound class.",

keywords = "CYP17A1, Cytochrome P450 17A1, Enzyme inhibition, Prostate cancer",

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AU - Wróbel, Tomasz M.

AU - Rogova, Oksana

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AU - Velazquez, Maria Natalia Rojas

AU - Pandey, Amit V.

AU - Jørgensen, Flemming Steen

AU - Arendrup, Frederic S.

AU - Andersen, Kasper L.

AU - Björkling, Fredrik

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N2 - Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC50 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure–activity relationship of this novel non-steroidal compound class.

AB - Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC50 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure–activity relationship of this novel non-steroidal compound class.

KW - CYP17A1

KW - Cytochrome P450 17A1

KW - Enzyme inhibition

KW - Prostate cancer

U2 - 10.3390/biom12020165

DO - 10.3390/biom12020165

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AN - SCOPUS:85122924205

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