Design of small molecules targeting I-BAR proteins.

Missing in metastasis (MIM, also MTSS1) is a member of the inverse Bin-Amphiphysin-Rvs (I-BAR) family that senses and stabilizes negative membrane protrusions. Abnormal expression of MIM has been frequently associated with a subset of human cancers and may play different roles in different stages of tumor progression. Overexpression of MIM-I-BAR in 293A cells potentiated the cell growth and increased the toxic response to paclitaxel. To modulate the function of MIM within cells, we designed several short peptide derivatives to target I-BAR dimerization. One of these derivatives had a cyclic configuration with a potency to disrupt the dimerization of MIM or ABBA proteins in vitro, and to be readily internalized into cells. Exposure of cells expressing MIM-I-BAR to this compound abolished increased susceptibility to paclitaxel and partially inhibited the I-BAR-mediated endocytosis. Our data suggests that this cyclic peptide can be used as a tool to study the function of intracellular MIM and as a lead to develop a therapy targeting human diseases involving abnormal MIM expressions.