Cancer Metastasis

Figure 1. Ca2+ dependent NMIIA-S100A4 interaction.
(A) The structure of apo, CA2+, and NMIIA1893-1928 bound S100A4 have been solved showing a hyrdrophobic cleft in S100A4 revealed upon Ca2+ binding that interacts with NMIIA. One monomer of the S100A4 dimer is shown in red and the other in blue with the hydrophobic residues that contact the NMIIA shown in yellow.
(B) Model of NMIIA shows the position of NMIIA1983-1926

Metastases are the cause of 90% of cancer deaths, but unfortunately, cancer therapy is lacking effective anti-metastasis drugs [1, 2]. This is because tumor cell invasion and metastasis are complex multi-step cellular processes in which malignant cells escape from the primary tumor and migrate to establish tumors at distant sites.  One marker of metastatic tumors is the S100 protein S100A4, which is also called mts1 (metastasin 1). However, S100A4 is not only a prognostic marker for metastasis in human cancers, but it has a direct role in promoting metastatic disease through its calcium dependent interaction with non-muscle myosin IIA (NMIIA) (Figure 1). Thus, the NMIIA-S100A4 complex is an ideal target for developing anti-metastasis drugs to treat multiple types of cancer.

A multifaceted approach is being taken to inhibit the NMIIA-S100A4 protein interaction to prevent tumor metastasis. First, the high resolution 3D structures of S100A4 have been determined at CBT and are being used for in silico screening of ~8 million compounds. Using state-of-the-art computational approaches developed by CBT CADD section leader Dr. Alexander MacKerell termed “Site Identification by Ligand Competitive Saturation (SILCS)” [3, 4]  is being done in conjunction with a SILCS-PHARMA approach [5]. Secondly, a fluorescence polarization competition assay has been developed and it being used to screen thousands of small drug-like compound libraries to identify inhibitors in the CBT Target Validation and Screening section.