Compounds targeting NF-kappaB activation as cancer therapeutics by inhibiting IkappaBalpha binding to beta-TrCP – Onco-kappaB

NF-kB is a pivotal transcription factor which activates the transcription of a great number of genes, including growth factors, angiogenesis factors, cell adhesion molecules, and anti-apoptotic factors . NF-kB controls the inflammatory response and other stressful situations. Activation of NF-kB is also the hallmark of the innate immune response and, owing to the subsequent induction of cytokines, chemokines, specific enzymes and anti-microbial peptides, NF-kB helps to construct the first line of defence against pathogens. Furthermore, NF-kB has an important role in the development of the acquired immune system, mainly as a result of its anti-apoptotic effect. Abnormally high constitutive activation of NF-kB is implicated in all chronic inflammatory syndromes, and inhibition of NF-kB activation pathways is one of the favourite targets for the development of a new generation of anti-inflammatory molecules.
NF-kB is also a key player in the etiology of human cancers. NF-kB is constitutively actived in various solid tumors (e.g. breast, ovarian, colon, pancreatic tumors), and hematopoietic malignancies (e.g. B and T-cell lymphomas) .It has been shown to promote tumor cell survival and reduce the effectiveness of conventional anticancer therapies . Hence, targeting NF-kB activation pathways would help also to develop new anti cancer drugs and/or new treatments potentiating the sensitivity of tumors to radiotherapy and chemotherapy. Proteasome inhibition has already been shown to block the chemotherapy-induced activation of NF-kB in vitro, and has been correlated with enhanced chemosensitivity and increased apoptosis in xenografted tumor cells in mice. Similarly, inhibition of NF-kB activation increases radiation-induced apoptosis and enhances the radiosensitivity of cancer cells, such as colorectal cancer cells both in vitro and in vivo.It thus appear that one crucial step in NF-kB activation is IkBs/b-TrCP protein-protein interaction. Our project main goal is to develop new inhibitory molecules that will target abnormal NF-kB activation through the inhibition of IkBs/b-TrCP interaction. Hopefully, such an approach should provide means to develop new strategies for therapeutic intervention in carcinogenesis and inflammatory diseases.
The project is built on a collaboration between :
- a biotechnology company, based at Genopole, CellVir (partner 1), Start up Biopharma specialized in the development of new drugs by inhibition of protein-protein interactions ;
- and two academic laboratories : that lead by Véronique Baud (partner 2) at the Institut Cochin, recognized as a world expert on the NF-kB activation pathways, member of the NF-kB study group in the Cancéropole Ile de France, and that of Gildas Bertho (partner 3), at UMR 8601 in Paris Descartes University, specialized in the structural study by NMR of the binding of small ligands to proteins and that has worked for several years with Richard Benarous to study by NMR techniques the binding of substrates to b-TrCP, including IkBa.
This industrial R&D program is validated by in vitro and in cellulo proof of concept previously obtained by the three partners of the project (see below), that the inhibition of the interaction between IkBa and its ubiquitin ligase b-TrCP results indeed in the blocking of the activation of NF-kB by potent stimulating agents such as TNFa.
The partners will be helped by subcontractant experts in high content in cellulo screenings ( Biophenics), and in xenotransplantation of human tumors in mice (Xentech).