Abstract C46: Design, synthesis, and functional evaluation of leukocyte-function associated antigen-1 (LFA-1) antagonists in early and late stages of cancer development.

Abstract

Abstract The integrin Leukocyte Function-associated Antigen-1 (LFA-1) recognizes and binds the Intercellular Adhesion Molecule-1 (ICAM-1) by its L chain Inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report here the rational in silico design, small scale synthesis and biological activity evaluation of a novel family of potent LFA-1 antagonists. The structure-based design led to the synthesis of a family of highly substituted homoquiral pyrrolidines that mimic key residues of the ICAM-1 moiety. Some of these compounds showed both antiproliferative and anti-metastatic activity in a murine model of melanoma, as well as potent anti-adhesive properties in several cancer cell lines in the low micromolar range. The molecular mechanism of action of selected antagonists have been investigated by NMR analysis of their binding to the isolated I-domain of LFA-1. We show that the compounds 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 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C46.