| Autor: |
Adhikari A, Teijaro CN, Yan X, Chang CY, Gui C, Liu YC, Crnovcic I, Yang D, Annaval T, Rader C, Shen B |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2020 Aug 13; Vol. 63 (15), pp. 8432-8441. Date of Electronic Publication: 2020 Jul 24. |
| DOI: |
10.1021/acs.jmedchem.0c00799 |
| Abstrakt: |
The enediynes are among the most cytotoxic molecules known, and their use as anticancer drugs has been successfully demonstrated by targeted delivery. Clinical advancement of the anthraquinone-fused enediynes has been hindered by their low titers and lack of functional groups to enable the preparation of antibody-drug conjugates (ADCs). Here we report biochemical and structural characterization of TnmH from the tiancimycin (TNM) biosynthetic pathway, revealing that (i) TnmH catalyzes regiospecific methylation at the C-7 hydroxyl group, (ii) TnmH exhibits broad substrate promiscuity toward hydroxyanthraquinones and S-alkylated SAM analogues and catalyzes efficient installation of reactive alkyl handles, (iii) the X-ray crystal structure of TnmH provides the molecular basis to account for its broad substrate promiscuity, and (iv) TnmH as a biocatalyst enables the development of novel conjugation strategies to prepare antibody-TNM conjugates. These findings should greatly facilitate the construction and evaluation of antibody-TNM conjugates as next-generation ADCs for targeted chemotherapy. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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