Design, Synthesis and Functional Evaluation of Leukocyte- Function Associated Antigen-1 (LFA-1) Antagonists in Early and Late Stages of Cancer Development.

Design, Synthesis and Functional Evaluation of Leukocyte- Function Associated Antigen-1 (LFA-1) Antagonists in Early and Late Stages of Cancer Development. Journal of Medicinal Chemistry 2013, vol 56, pp. 735-747.

http://pubs.acs.org/doi/abs/10.1021/jm3016848

Abstract: The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its αL-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.