ENT-21

ENT-21 is an orally bioavailable small molecule prodrug of ENT-03, a centrally acting allosteric inhibitor of protein-tyrosine phosphatase 1B (PTP1B). Developed for the treatment of obesity and type 2 diabetes, ENT-21 is designed to improve metabolic health by enhancing hypothalamic insulin and leptin signaling. Upon oral administration, ENT-21 is rapidly converted into ENT-03, which binds to a specific allosteric site on PTP1B comprised of the α3, α6, and α7 helices. This binding induces a conformational change in the W-P-D loop of the enzyme, rendering the catalytic site inoperable. This allosteric mechanism provides high selectivity for PTP1B over other tyrosine phosphatases such as SHP2, potentially avoiding the off-target effects that have hindered previous PTP1B inhibitor development programs.