C-terminal Binding Proteins (CtBP) 1 and 2 are oncogenic transcriptional co-regulators overexpressed in many cancer types, with their expression level correlating to worse prognostic outcomes and aggressive tumor features. CtBP negatively regulates the expression of many tumor suppressor genes, while coactivating genes that promote proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal activity. In light of this evidence, the development of novel inhibitors that mitigate CtBP function may provide clinically actionable therapeutic tools. This review article focuses on the progress made in understanding CtBP structure, role in tumor progression, and discovery and development of CtBP inhibitors that target CtBP's dehydrogenase activity and other functions, with a focus on the theory and rationale behind the designs of current inhibitors. We provide insight into the future development and use of rational combination therapy that may further augment the efficacy of CtBP inhibitors, specifically addressing metastasis and cancer stem cell populations within tumors.

Combretastatin A-4 (CA4) is highly potent anticancer drug that acts as an inhibitor of tubulin polymerization. The core of the CA4 structure contains a cis-stilbene, and it is known that the trans isomer is significantly less potent. We prepared an azobenzene analog of CA4 (Azo-CA4) that shows 13–35 fold enhancement in potency upon illumination. EC50 values in the light were in the mid nM range. Due to its ability to thermally revert to less toxic trans form, Azo-CA4 also has the ability to automatically turn its activity off with time. Azo-CA4 is less potent than CA-4 because it degrades in the presence of glutathione as evidenced by UV-Vis spectroscopy and ESI-MS. Nevertheless, Azo-CA4 represents a promising strategy for switchable potency for treatment of cancer.

Light is used to release a drug from a cell impermeable small molecule, uncloaking its cytotoxic effect on cancer cells.

C-terminal binding proteins 1 and 2 (CtBP1 and CtBP2) are transcriptional regulators that activate or repress many genes involved in cellular development, apoptosis and metastasis. CtBP proteins are activated under hypoxic conditions where NAD(H) levels tend to be higher. NADH-dependent activation of CtBP2 has direct implication in multiple types of cancers and poor patient prognosis. Previous studies have proposed dimeric CtBP as the relevant oligomeric state, however our studies with multi-angle light scattering have shown that the primary effect of NADH binding is to promote the assembly of two CtBP dimers into tetramers. Here, we present the cryoEM structures of two different constructs of CtBP2 corroborating that the native state of CtBP2 in the presence of NADH is indeed tetrameric. The physiological relevance of tetrameric CtBP2 was tested in HCT116; CtBP2 -/-cells transfected with tetramer destabilizing mutants.Mutants that inhibit tetramer formation show a decrease in expression of the CtBP transcriptional target TIAM1 and exhibit a decrease in the ability to promote cell .

A new reaction-based fluorescent reporter for H2S has been developed based on 8-aminopyrene-1,3,6-trisulfonate. This reporter shows high selectivity for H2S over other ions and thiols, and can detect H2S directly in serum without additives.