Multiple myeloma (MM) is a cancer of plasma cells, a type of white blood cells normally responsible for producing antibodies.In MM, collections of abnormal plasma cells accumulate in the bone marrow where they receive proliferative, survival, and migratory signals from the bone marrow microenvironment. Insulin-like growth factor 1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) widely expressed in normal tissues where it functions in growth regulation. Studies showed that IGF-1R stimulates the proliferation and survival of MM cells as well as their migration, adhesion, and invasion. Therefore, inhibition of IGF-1R represents an attractive therapeutic target for MM. We designed and synthesized a novel small-molecule IGF-1R inhibitor GTx-134 on the basis of IGF-1R protein-inhibitor co-crystal X-ray structure and computational modeling. GTx-134, as a dual inhibitor of IGF-1R and insulin receptor (IR), reduces autophosphorylation of its target receptor and inhibits signaling through the PI3k/Akt pathway. GTx-134 induces apoptosis of primary patient MM cells and effectively reduces tumor burden in a HMCL xenografts model.

Design and synthesis of GTx-134, a highly selective dual IGF-1R and insulin receptor (IR) inhibitor

248th National Meeting (2014)

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