Design, synthesis, and functional evaluation of leukocyte function associated antigen-1 antagonists in early and late stages of cancer development.

Abstract

The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its α(L)-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.

• Authors: Eider San Sebastián, Tahl Zimmerman, Aizpea Zubia, Yosu Vara, Elyette Martin, Finton Sirockin, Annick Dejaegere, Roland H Stote, Xabier Lopez, David Pantoja-Uceda, María Valcárcel, Lorea Mendoza, Fernando Vidal-Vanaclocha, Fernando P Cossío, Francisco J Blanco
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 3 Pg. 735-47 (Feb 14 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23339734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lymphocyte Function-Associated Antigen-1

Topics

• Cell Line, Tumor
• Drug Design
• Humans
• Lymphocyte Function-Associated Antigen-1 (drug effects)
• Models, Molecular
• Neoplasms (physiopathology)
• Structure-Activity Relationship