TY - JOUR
T1 - Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents
AU - Wróbel, Tomasz M.
AU - Rogova, Oksana
AU - Sharma, Katyayani
AU - Velazquez, Maria Natalia Rojas
AU - Pandey, Amit V.
AU - Jørgensen, Flemming Steen
AU - Arendrup, Frederic S.
AU - Andersen, Kasper L.
AU - Björkling, Fredrik
N1 - Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022
Y1 - 2022
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
M3 - Journal article
C2 - 35204665
AN - SCOPUS:85122924205
VL - 12
JO - Biomolecules
JF - Biomolecules
SN - 2218-273X
IS - 2
M1 - 165
ER -