Targeting Protein-protein interactions with novel small molecules: Phenotypical and Rational approaches for cancer therapy

Protein-Protein Interactions (PPI) are physical interactions between proteins that play a key role in the regulation of a myriad of cellular processes regarding development, metabolism, growth and survival. One protein can contact a vast pool, named interactome, of partner proteins by interacting with them and causing conformational changes that can enhance, reduce or even alter their function. In light of the above, PPI offer an interesting target to exploit in cancer therapy as a therapeutic approach “parallel” to kinase inhibitors. In particular, modulation of the activity of a family of regulatory hub proteins, called 14-3-3, has recently sparked attention since all their seven isoforms interact with proteins involved in the regulation of cancer cell proliferation, cell cycle, apoptosis, and DNA synthesis. Following a phenotypic drug discovery approach, our research group recently came up with a novel small molecule hit compound, named FC86, with a nanomolar in vitro and in vivo anticancer activity and low toxicity. A target deconvolution campaign revealed 14-3-3 proteins as a target for FC86. For hit-to-lead optimization a small library of FC86 analogues was synthesized, characterized and subsequently tested with SPR and MST to estimate binding with 14-3-3ζ. PPI are also involved in Hematological cancer, as T-Cell Leukemia/Lymphoma 1(TCL1) is a protein capable of enhancing AKT pathway promoting T-cell proliferation and cooperate to the activation of the BCR pathway. Our research group used a rational approach to design and synthesize a small library of hit compounds with a putative dual activity on TCL1 and Bruton Tyrosine Kinase (BTK), one of the most regarded targets for lymphoma therapy. Molecular modeling and docking computational studies identified a class of quinazolone based compounds, namely NFS, that demonstrated a good antiproliferative activity when tested on Lymphoma cell lines and subedued to Saturation Transfer Difference (STD) NMR to investigate TCL1 binding.