C3 ester side chain plays a pivotal role in the antitumor activity of Maytansinoids.
Biochem Biophys Res Commun
; 566: 197-203, 2021 08 20.
Article
in En
| MEDLINE
| ID: mdl-34144258
ABSTRACT
Maytansinoids, the chemical derivatives of Maytansine, are commonly used as potent cytotoxic payloads in antibody-drug conjugates (ADC). Structure-activity-relationship studies had identified the C3 ester side chain as a critical element for antitumor activity of maytansinoids. The maytansinoids bearing the methyl group at C3 position with D configuration were about 100 to 400-fold less cytotoxic than their corresponding L-epimers toward various cell lines. The detailed mechanism of how chirality affects the anticancer activity remains elusive. In this study, we determined the high-resolution crystal structure of tubulin in complex with maytansinol, L-DM1-SMe and D-DM1-SMe. And we found the carbonyl oxygen atom of the ester moiety and the tail thiomethyl group at C3 side chain of L-DM1-SMe form strong intramolecular interaction with the hydroxyl at position 9 and the benzene ring, respectively, fixing the bioactive conformation and enhancing the binding affinity. Additionally, ligand-based and structure-based virtually screening methods were used to screen the commercially macrocyclic compounds library, and 15 macrocyclic structures were picketed out as putatively new maytansine-site inhibitors. Our study provides a possible strategy for the rational discovery of next-generation maytansine site inhibitors.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tubulin
/
Maytansine
/
Antineoplastic Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
Biochem Biophys Res Commun
Year:
2021
Type:
Article