title: 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: Ikerchem Ltd., 20009 San Sebastián, Spain.
authors: Eider
authors: E
authors: San Sebastián
authors: Tahl
authors: T
authors: Zimmerman
authors: Aizpea
authors: A
authors: Zubia
authors: Yosu
authors: Y
authors: Vara
authors: Elyette
authors: E
authors: Martin
authors: Finton
authors: F
authors: Sirockin
authors: Annick
authors: A
authors: Dejaegere
authors: Roland H
authors: RH
authors: Stote
authors: Xabier
authors: X
authors: Lopez
authors: David
authors: D
authors: Pantoja-Uceda
authors: María
authors: M
authors: Valcárcel
authors: Lorea
authors: L
authors: Mendoza
authors: Fernando
authors: F
authors: Vidal-Vanaclocha
authors: Fernando P
authors: FP
authors: Cossío
authors: Francisco J
authors: FJ
authors: Blanco
mesh_terms: D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D008958:Models, Molecular; D009369:Neoplasms / Q000503:physiopathology*; D013329:Structure-Activity Relationship
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1