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

San Sebastian, Eider and Zimmerman, Tahl and Zubia, Aizpea and Vara, Yosu and Martin, Elyette and Sirockin, Finton and Dejaegere, Annick and Stote, Roland H and Lopez, Xabier and Pantoja-Uceda, David and Varcarcel, Maria and Medoza, Lorea and Vidal-Vanaclocha, Fernando and Cossío, Fernando P. and Blanco, Francisco J. (2013) Design, Synthesis and Functional Evaluation of Leuko-cyte-Function Associated Antigen-1 (LFA-1) Antagonists in Early and Late Stages of Cancer Development. Journal of Medicinal Chemistry, 56 (3). pp. 735-747. ISSN 0022-2623

Abstract

The integrin Leukocyte Function-associated Antigen-1 (LFA-1) recognizes and binds the Intercellular Adhesion Molecule-1 (ICAM-1) by its alpha 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 antimetastatic activity in a murine model of melanoma, as well as potent antiadhesive 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, in the isolated I-domain, 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.

Item Type: Article
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Additional Information: A paid open access option is available for this journal. Archiving not formally supported.
Keywords: LFA-1 antagonists, allosteric effects, pyrrolidines, [3+2] cycloaddition, NMR, cancer, metastasis, angiogenesis
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9079

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