期刊
BIOMOLECULES
卷 13, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/biom13061002
关键词
ATSP-7041; MDM2; MDMX inhibitor; & alpha;-helical peptide; drug-drug interaction
ATSP-7041 is a promising modality targeting protein-protein interactions, but data on its drug-drug interaction potential are scarce. It was found that ATSP-7041 has negligible metabolism and limited inhibition of CYP activities, but it strongly inhibits the activities of OATPs, P-gp, and BCRP. Furthermore, it was demonstrated that ATSP-7041 is a substrate and strong inhibitor of OATP1B1 activity. These findings highlight the transporter-mediated DDI potential of high molecular weight stapled peptides and the necessity for their evaluation in drug development.
ATSP-7041, a stapled a-helical peptide that inhibits murine double minute-2 (MDM2) and MDMX activities, is a promising modality targeting protein-protein interactions. As peptides of molecular weights over 1000 Da are not usually evaluated, data on the drug-drug interaction (DDI) potential of stapled a-helical peptides remain scarce. Here, we evaluate the interaction of ATSP-7041 with hepatic cytochrome P450s (CYPs; CYP1A2, CYP2C9, CYP2C19, CYP3A4, and CYP2D6) and transporters (organic anion transporting polypeptides (OATPs; OATP1B1 and OATP1B3), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP)). ATSP-7041 demonstrated negligible metabolism in human liver S9 fraction and a limited inhibition of CYP activities in yeast microsomes or S9 fractions. On the contrary, a substantial uptake by OATPs in HEK 293 cells, a strong inhibition of OATP activities in the cells, and an inhibition of P-gp and BCRP activities in reversed membrane vesicles were observed for ATSP-7041. A recent report describes that ALRN-6924, an ATSP-7041 analog, inhibited OATP activities in vivo; therefore, we focused on the interaction between ATSP-7041 and OATP1B1 to demonstrate that ATSP-7041, as a higher molecular weight stapled peptide, is a substrate and strong inhibitor of OATP1B1 activity. Our findings demonstrated the possibility of transporter-mediated DDI potential by high molecular weight stapled peptides and the necessity of their evaluation for drug development.
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