Matthew Glenn

Targeting protein-protein interactions: suppression of Stat3 dimerization with rationally designed small-molecule, nonpeptidic SH2 domain binders.

Protein-protein interactions remain a daunting target for disruption by small molecules due to their large interfacial areas and their often noncontiguous contact points. The prospect for inhibition increases when small interaction modules (such as SH2 domains) participate in the binding. SH2 domains are found in the family of signal transducers and activators of transcription (STAT) proteins,[1] which mediate the relay of extracellular signals from various cell-surface protein receptors to the nucleus, where they help to initiate and regulate specific gene expression.[2] In particular, the Stat3 protein is known to directly upregulate Bcl-xL, c-Myc, Mcl-1, VEGF, and cyclin D1/D2, and contributes directly to compromised cellular regulation by stimulating cell proliferation and preventing apoptosis in numerous human cancers.[2,3]

Non-peptidic substrate-mimetic inhibitors of Akt as potential anti-cancer agents

Akt has emerged as a critical target for the development of anti-cancer therapies. It has been found to be amplified, overexpressed, or constitutively activated in numerous human malignancies with oncogenesis derived from the simultaneous promotion of cell survival and suppression of apoptosis. A valuable alternative to the more common ATP-mimetic based chemotherapies is a substrate-mimetic approach, which has the potential advantage of inherent specificity of the substrate-binding pocket. In this paper we present the development of high affinity non-peptidic, substrate-mimetic inhibitors based on the minimum GSK3beta substrate sequence. Optimization of initial peptidic leads resulted in the development of several classes of small molecule inhibitors, which have comparable potency to the initial peptidomimetics, while eliminating the remaining amino acid residues. We have identified the first non-peptidic substrate-mimetic lead inhibitors of Akt 29a-b, which have affinities of 17 and 12 microM, respectively. This strategy has potential to provide a useful set of molecular probes to assist in the validation of Akt as a potential target for anti-cancer drug design.