Background:

BT-11 is an orally available LANCL2 binding compound for treating inflammatory bowel disease.

LANCL2 engagement produces an increase of PKA, followed by an accumulation of cAMP in the cytoplasm. BT-11 treatment splenocytes shows a dose-response increase of cAMP production. BT-11 stimulates cAMP production by activating the LANCL2 pathway[1].

The oral treatment with BT-11 (8 mg/kg/d) in a mouse model of inflammatory bowel disease results in lowering the disease activity index, decreasing colonic inflammatory lesions by 4-fold, and suppressing inflammatory markers (e.g., TNF-α, and interferon-γ) in the gut. Furthermore, studies in LANCL2-/- mice demonstrates that loss of LANCL2 abrogates beneficial actions of BT-11, suggesting high selectivity for the target. Oral treatment with BT-11 (8 mg/kg/day) ameliorates colitis in mice. Initial safety assessment in rats indicates that oral treatment with BT-11 at high doses has an excellent safety profile up to 1000 mg/kg/day[1]. BT-11 is well tolerated in rats, and may hold promise as an orally active therapeutic for Crohn’s disease. One hour after oral administration of a single dose of 80 mg/kg, BT-11 has a maximal concentration of 21 ng/mL; the half-life is 3 hours[2].

[1]. Carbo A, et al. An N,N-Bis(benzimidazolylpicolinoyl)piperazine (BT-11): A Novel Lanthionine Synthetase C-Like 2-Based Therapeutic for Inflammatory Bowel Disease. J Med Chem. 2016 Nov 23;59(22):10113-10126. [2]. Bissel P, et al. Exploratory Studies With BT-11: A Proposed Orally Active Therapeutic for Crohn’s Disease. Int J Toxicol. 2016 Sep;35(5):521-9.