Document Report Card

ID: ALA2311462

Journal: J Med Chem

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

Authors: San Sebastián E, Zimmerman T, Zubia A, Vara Y, Martin E, Sirockin F, Dejaegere A, Stote RH, Lopez X, Pantoja-Uceda D, Valcárcel M, Mendoza L, Vidal-Vanaclocha F, Cossío FP, Blanco FJ.

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.

CiteXplore: 23339734

DOI: 10.1021/jm3016848