Gamma-secretase (presenilin complex)

Class

Small molecule (selective, reversible, noncompetitive gamma-secretase inhibitor)

Pathway

Blocks gamma-secretase-mediated proteolytic shedding of BCMA from the myeloma cell surface, increasing BCMA target density and enhancing the efficacy of BCMA-directed therapies (also affects Notch signaling, the basis of its separate desmoid-tumor approval)

Gamma-secretase is a multi-subunit enzyme complex built around a presenilin protein that cuts other proteins within their membrane-spanning segment, a process known as regulated intramembrane proteolysis. It acts on many different transmembrane proteins, including Notch receptors and B-cell maturation antigen (BCMA), a surface receptor found on normal plasma cells and on malignant cells in multiple myeloma. In myeloma, gamma-secretase continuously clips BCMA from the tumor cell surface and releases it into the bloodstream, reducing the amount of intact receptor available as a target for BCMA-directed immunotherapies such as antibody-drug conjugates, bispecific antibodies, and engineered T-cell therapies. Blocking gamma-secretase prevents this shedding, raising the density of BCMA on the tumor cell surface and thereby increasing the effectiveness of those BCMA-targeted treatments when used together. Separately, because the same enzyme also processes Notch receptors to release a fragment that drives cell growth signaling, inhibiting it reduces Notch pathway activity, which matters in conditions driven by excessive Notch signaling, such as desmoid tumors, a locally aggressive but non-metastatic soft-tissue growth. This dual biology shows how one enzymatic target can be therapeutically relevant through entirely different mechanisms in different diseases.