Autoimmune disease is commonly treated with steroids and/or immune-suppressants, which have side effects disfavouring chronic use. While biologics have been introduced in diseases such as RA, psoriasis, and SLE, these are expensive injectable treatments, and generally result in risk of serious infections. There is therefore a large unmet need for a safe chronic oral treatment for autoimmune disease.
BET bromodomain inhibitors lower production of numerous cytokines and show efficacy in diverse autoimmune disease models. Several BET inhibitors are in clinical trials within oncology, but these compounds induce strong haematological and GI side effects that preclude their use for chronic treatment of autoimmune disease. Humans express 4 BET proteins (BRD2, 3, 4, and –T), each containing 2 bromodomains (BD1 and BD2). The oncology BET inhibitors inhibit all 8 BET bromodomains without apparent selectivity. Emerging data suggest that BD1 and BD2 have different functions, and recently a BD1-preferring compound was shown to inhibit TH17 differentiation without affecting other T cell subsets.
Here we describe NUE7770, a small molecule with high affinity for BET BD1 and strong selectivity against BD2 and other bromodomains. In a panel of primary human cell based assays, NUE7770 strongly suppressed IL-17 and IgG secretion in B/T cell co-cultures with negligible activity in other assays. In vivo, NUE7770 dose-dependently inhibited auto-antibody production in two independent models of lupus, and showed strong therapeutic efficacy on par with IL-17A neutralization in the TH17-driven CIA model. A two-week toxicology study in mice demonstrated that constant suppression of BD1 by NUE7770 is safe with no adverse findings. This is in stark contrast to simultaneous BD1/2 suppression using the pan-BET inhibitor JQ1, which leads to multiple toxicological findings, including lethality. Taken together, BD1 inhibitors like NUE7770 may potentially offer safe chronic oral treatments for autoimmune diseases such as psoriasis and SLE.