title: An N,N-Bis(benzimidazolylpicolinoyl)piperazine (BT-11): A Novel Lanthionine Synthetase C-Like 2-Based Therapeutic for Inflammatory Bowel Disease.
abstract: Lanthionine synthetase C-like 2 (LANCL2), a novel therapeutic target for inflammatory and autoimmune diseases and diabetes, exerts anti-inflammatory and insulin-sensitizing effects. This study reports the first LANCL2-based therapeutics for inflammatory bowel disease (IBD). Analogues of 1 (ABA) and 2 (NSC61610) were screened by molecular docking, then synthesized and analyzed for binding to LANCL2 by surface plasmon resonance. Piperazine-1,4-diylbis(6-benzo[d]imidazole-2-yl)pyridine-2-yl)methanone, 7, was identified as the lead LANCL2-binding compound for treating IBD. The oral treatment with 7 (8 mg/kg/d) in a mouse model of IBD resulted 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 demonstrated that loss of LANCL2 abrogated beneficial actions of 7, suggesting high selectivity for the target. In conclusion, 7 merits continued development as a LANCL2-based, first-in-class orally active therapeutic for IBD.
authors.affiliation: Biotherapeutics Inc. , 1800 Kraft Drive, Suite 200, Blacksburg, Virginia 24060, United States.
authors.forename: Adria
authors.initials: A
authors.lastname: Carbo
authors.affiliation: Biotherapeutics Inc. , 1800 Kraft Drive, Suite 200, Blacksburg, Virginia 24060, United States.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gandour
authors.affiliation: Biotherapeutics Inc. , 1800 Kraft Drive, Suite 200, Blacksburg, Virginia 24060, United States.
authors.forename: Raquel
authors.initials: R
authors.lastname: Hontecillas
authors.affiliation: Biotherapeutics Inc. , 1800 Kraft Drive, Suite 200, Blacksburg, Virginia 24060, United States.
authors.forename: Noah
authors.initials: N
authors.lastname: Philipson
authors.affiliation: Georgetown University Medical Center , Washington, District of Columbia 20057, United States.
authors.forename: Aykut
authors.initials: A
authors.lastname: Uren
authors.affiliation: Biotherapeutics Inc. , 1800 Kraft Drive, Suite 200, Blacksburg, Virginia 24060, United States.
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D028044:Phosphate-Binding Proteins; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C572254:LANCL2 protein, mouse; D008565:Membrane Proteins; C000620073:N,N-bis(benzimidazolylpicolinoyl)piperazine; D028044:Phosphate-Binding Proteins; D010879:Piperazines; D011956:Receptors, Cell Surface