Novel c-Rel Inhibitors as therapies for Cancer, Inflammatory Disease, Autoimmune Diseases and Transplantation Rejection

Diseases of the immune cells encompass broad categories of disorders including inflammation (e.g. asthma), autoimmune diseases (e.g. rheumatoid arthritis, type I diabetes, psoriasis and multiple sclerosis), and B cell tumors (e.g. Hodgkin's lymphoma, CLL, multiple myeloma, diffuse large cell lymphoma). The drugs for immune disorders have a combined $40 billion market. While corticosteroids have been widely used for treating immune disorders, they cause severe systemic side effects that preclude their chronic administration. Antibody therapies have been successfully introduced for immune disorders, but they are expensive, require injection or infusion and compromise protective immunity. There is a need for anti-inflammatory and cancer therapies that are relatively inexpensive and can be safely administered for chronic use. Inhibitors of c-Rel, a member of the NF-B/Rel family of transcription factors, appear to have potential to meet that need.

Dr. Hsiou-Chi Liou and colleagues have extensively investigated the function of c-Rel, predominantly through the studies of c-Rel knock-out mice which do not appear to exhibit systemic toxicity or any other readily recognizable abnormality. C-Rel proto-oncogene is one of the immediate early transcription factors induced in lymphocytes and myeloid cells during an inflammatory response. Atypical constitutive c-Rel activation is highly associated with the development of leukemia, lymphoma, and solid tumors such as breast cancer. The inflammatory and tumorigenic potential of c-Rel is mediated by its target genes, which include multiple inflammatory cytokines, growth factors, cell cycle regulators, and anti-apoptotic molecules.

Studies on the c-Rel knockout mice indicate that blocking c-Rel activity in mice ameliorates allergic asthma, multiple sclerosis, type I diabetes, and arthritis. Moreover, the c-Rel knockout mice tolerated allografts in both cardiac and pancreatic transplantation models. Using a screen to find compounds that directly inhibit the binding of c-Rel to its DNA target, several molecular scaffolds were identified and subjected to SAR analysis leading to the development of proprietary c-Rel inhibitors that have shown (i) potent efficacy in animal models; (ii) the ability to block multiple cytokine production simultaneously; and (iii) a broad application to diseases treated by corticosteroids including lymphomas. Selected proprietary compounds with drug-like potency have been found to be efficacious in mouse models of: (i) multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)) a (2) graft versus host disease (GVHD) and (iii) xenograft models of diffuse large B-cell lymphoma.

Potential Applications

Small molecule inhibitors for the treatment of cancer, inflammatory disease, autoimmune diseases, transplantation rejection and osteoporosis

Advantages

• Small molecule inhibitors of c-Rel would be more effective and less expensive than antibody based therapies targeting a single cytokine
• Small molecule inhibitors of c-Rel are less compromising of protective immunity
• Small molecule inhibitors of c-Rel could potentially be used chronically