Chemical Modulation of Phospho-Signaling Pathways Involved in Cancer.

Abstract

Advancements in our understanding of the molecular causes of cancer have led to the therapeutic targeting of key enzymes involved in cell growth. Kinase inhibitors have been the most successful forms of such targeted therapy for a select group of cancers. However, a comprehensive understanding of the biological roles of individual kinases is necessary for therapies to be effective in a majority of cancers. Thus, the development of selective kinase inhibitors is essential for continued improvement in cancer chemotherapy. Additionally, the exploration of non-kinase targets is indispensable in adding to the toolbox of effective anti-cancer agents. To increase the number of tools available for targeted therapy, we aimed to develop selective inhibitors for critical proteins involved in phospho-signaling pathways. Our studies include the development of an inhibitor of the fusion protein, Bcr-Abl, which is the primary driver of Chronic Myelogenous Leukemia (CML). Most current FDA-approved drugs are ineffective against a resistant form of CML bearing a T315I mutation in the kinase domain of Bcr-Abl. Through a hypothesis based on the prevailing model of selectivity, we developed an extremely selective compound with high potency for both the wild-type and mutant forms of Bcr-Abl. The adaptor protein Grb2 is an under-explored, non-kinase target for the treatment of CML and other cancers. Our efforts for targeting Grb2 centered on the hypothesis that utilizing conformational constraint for inhibitor development could lead to compounds with increased potency due to a lowered entropic cost of binding. Through the systematic development of conformationally constrained cyclic peptides, we identified a novel scaffold for the inhibition of Grb2 with in cellulo efficacy in a CML cell line. Lastly, while protein kinases have been traditionally targeted with small molecules directed to their ATP-binding site, targeting the peptide substrate-binding site of kinases offers an attractive alternative with several advantages. Our efforts attempted to circumvent the problems typically associated with substrate-competitive inhibitors by covalently inhibiting the target Akt1 kinase. As a whole, results from this dissertation should advance the development of potent and selective inhibitors and aid in the understanding of signaling pathways involved in cancer.