Second generation MTI-101 analogs using a novel peptoid-peptide hybrid beta-hairp

MTI-101 is a cyclic beta-hairpin peptide that binds CD44 with high affinity and kills multiple myeloma cell lines in vitro and blocks the growth of myeloma tumors in 2 different murine models. This interaction of MTI-101 with the surface of MM cells causesprogrammed cell necrosis, whereas all approved MM drugs cause apoptosis and so the novel mechanism of MTI-101 or MTI-like compounds makes it especially attractive for further development. The focus of this application will be on the synthesis and biological evaluation of MTI- 101-like analogs based on a novel peptoid-peptide hybrid scaffold. The following Aims are also the Milestones for this phase I application; they must be completed before a phase II application can be submitted. Aim 1. We will preparefocused libraries that vary the norLeu group with at least 50 different primary amines. The one with the best binding and in vitro bioactivity will be left unchanged and in turn the Val and the Trp positions will be optimized with at least 50 different pr