Abstract 1559: Targeting the PH domain of Tiam-1 to inhibit breast cancer metastasis

Abstract

Abstract TIAM-1 (T-lymphoma invasion and metastasis-inducing protein-1) is a highly conserved guanine nucleotide exchange factor and contains an N-terminal pleckstrin homology domain (PHn) and a Dbl homology (DH)/C-terminal PH domain (PHc). While no crystal structure exists for the PHn of TIAM-1, the crystal structure of DH-PHc of TIAM-1 in complex with Rac-1 has been reported. TIAM-1 has been found to be over-expressed in breast, colon and prostate cancers. An increase in TIAM-1 expression has been shown to be associated with increased metastatic potential of breast cancer cell lines. TIAM-1 is thus an ideal PH domain drug target directly related to cancer progression, metastasis and patient survival. In this study, we have identified novel small molecule inhibitors targeting the phosphoinositide (PtdIns) lipid binding PHc domain of TIAM-1 in order to selectively inhibit cell migration and survival. Utilizing an In Silico screen of our internal and Maybridge library and the crystal structure of TIAM-1, we have found 29 compounds that bind to PHc TIAM-1. In vitro assays have revealed that compound PH-210 and #10 significantly reduced the amount of active Rac1 and binds to PHc-TIAM-1 with high affinity (KD in the micromolar range) using surface plasmon resonance (SPR) spectrometry. Both compounds displace PtdIns-3,4,5-P3 in a SPR competitive binding assay. Ongoing in vivo studies using MDA-231 breast cancer cell lines will determine the anti-tumor activity of these compounds. Overall, these novel compounds could exhibit the ability to significantly reduce breast cancer metastasis by binding to PHc-TIAM-1 and could have the potential to be used with other chemotherapeutic compounds as part of an effective breast cancer treatment regimen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1559.