Signal transducers and activators of transcription (STATs) are a family of latent cytoplasmic transcription factors that transmit signals from the cell membrane to the nucleus. One family member, STAT3, is constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of cancer cell lines and human tumors. Screening of chemical libraries led to the identification of Stattic, a nonpeptidic small molecule shown to selectively inhibit the function of the STAT3 SH2 domain regardless of the STAT3 activation state in vitro. Stattic selectively inhibits activation, dimerization, and nuclear translocation of STAT3 and increases the apoptotic rate of STAT3-dependent breast cancer cell lines. We propose Stattic as a tool for the inhibition of STAT3 in cell lines or animal tumor models displaying constitutive STAT3 activation.

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The serine/threonine kinase Polo-like kinase 1 (Plk1) is overexpressed in many types of human cancers, and has been implicated as an adverse prognostic marker for cancer patients. Plk1 localizes to its intracellular anchoring sites via its polo-box domain (PBD). Here we show that Plk1 can be inhibited by small molecules which interfere with its intracellular localization by inhibiting the function of the PBD. We report the natural product thymoquinone and, especially, the synthetic thymoquinone derivative Poloxin as inhibitors of the Plk1 PBD. Both compounds inhibit the function of the Plk1 PBD in vitro, and cause Plk1 mislocalization, chromosome congression defects, mitotic arrest, and apoptosis in HeLa cells. Our data validate the Plk1 PBD as an anticancer target and provide a rationale for developing thymoquinone derivatives as anticancer drugs.

In the current work, unanticipated synthetic byproducts were obtained arising from alkylation of the δ1 nitrogen (N3) of the histidine imidazole ring of the polo-like kinase-1 (Plk1) polo-box domain (PBD)-binding peptide PLHSpT. For the highest affinity byproduct, bearing a C6H5(CH2)8– group, a Plk1 PBD co-crystal structure revealed a new binding channel that had previously been occluded. An N-terminal PEGylated version of this peptide containing a hydrolytically-stable phosphothreonyl residue (pT) bound to the Plk1 PBD with affinity equal to the non-PEGylated parent, yet it exhibited significantly less interaction with the PBDs of the two closely-related Plk2 or Plk3. Treatment of cultured cells with this PEGylated peptide resulted in Plk1 delocalization from centrosomes and kinetochores, and chromosome misalignment that effectively induced mitotic block and apoptotic cell death. This work provides new insights that may advance efforts to develop Plk1 PBD-binding inhibitors as potential Plk1-specific anticancer therapeutic agents.

Many proteins exert their biological roles as components of complexes, and the functions of proteins are often determined by their specific interactions with other proteins. Because of the central importance of protein-protein interactions for cellular processes, the ability to interfere with specific protein-protein interactions provides a powerful means of influencing the function of selected proteins within the cell. Cell-permeable small organic modulators of protein-protein interactions are thus highly desirable tools both for the study of physiological cellular processes and for the treatment of numerous diseased states. Herein a number of protein-protein interactions that are considered to be pharmaceutical targets are presented, which will familiarize the reader with the strategies that have been employed for the successful identification of small molecule modulators of these protein-protein interactions. These encouraging examples suggest that combined research efforts in the areas of functional proteomics, assay development, and organic synthesis will open up novel possibilities for the treatment of human diseases in the future.