Protein-Protein Interactions and Cancer: Targeting the Central Dogma

Amanda      L. Garner; Kim      D. Janda

Abstract

Between 40,000 and 200,000 protein-protein interactions have been predicted to exist within the human interactome. As these interactions are of a critical nature in many important cellular functions and their dysregulation is causal of disease, the modulation of these binding events has emerged as a leading, yet difficult therapeutic arena. In particular, the targeting of protein-protein interactions relevant to cancer is of fundamental importance as the tumor-promoting function of several aberrantly expressed proteins in the cancerous state is directly resultant of its ability to interact with a protein- binding partner. Of significance, these protein complexes play a crucial role in each of the steps of the central dogma of molecular biology, the fundamental processes of genetic transmission. With the many important discoveries being made regarding the mechanisms of these genetic process, the identification of new chemical probes are needed to better understand and validate the druggability of protein-protein interactions related to the central dogma. In this review, we provide an overview of current small molecule-based protein-protein interaction inhibitors for each stage of the central dogma: transcription, mRNA splicing and translation. Importantly, through our analysis we have uncovered a lack of necessary probes targeting mRNA splicing and translation, thus, opening up the possibility for expansion of these fields.

Keywords: Cancer, mRNA splicing, protein-protein interactions, small molecules, transcription, translation, human interactome, genetic transmission, molecular biology, DNA, ribosome, non-peptidic molecules, embryogenesis, cell-to-cell communication, receptor-ligand interactions, signal transduction pathways, gene transcription, metabolism, homeostasis, hot spot, RNA polymerase II, co-repressors, chromatin re-modelers, histone acetylases, kinases, methylases, p53(H/M)DM2 Inhibitors, human tumors, tumor suppressor, apoptosis, DNA repair, tumorigenesis, N-terminal domain, MDM2, chalcone, ELISA, NMR, MCF-7, NCI-H446, sulfonamide, pharmacophore, cancer therapy, cis-imidazoline, Nutlin-3, nutlin-type analogue 7, benzodiazepinedione, TDP665759, doxorubicin, A375 melanoma cells, pentanoic acid, MI-43, LNCaP cells, tissue sarcoma, cyclin E, catenin, oncogene addiction, DMSO, Microdochium caespitosum, helix-loop-helix leucine zipper, Burkitt's lymphoma, colorectal cancers, colon carcinomas, CACGTG, zincfinger, FRET-based assay, mobility-shift assay, mycmicin-2, TCF-catenin, catenin CREB-binding protein, HIF p300, KID KIX, Runx1 CBF, EWS-FLI1 RNA helicase A, Hsp90 BCL-6, T-cell factor, APC complex, SW620 xenograft, acute myeloid leukemia, serine residue, Chaetomium, Core binding factor, coiled-coil domain, EWS-FLI1 RNA helicase, Topoisomerase I Kinase, histone acetylation, eIF4E Interactions