Therapies that inhibit multiple drivers of disease by targeting fundamental upstream control processes within the cell have the potential for profound therapeutic benefit in a number of difficult-to-treat diseases.
At Kezar, we are advancing two drug development programs harnessing different “master regulators” of cellular function: protein degradation, which is regulated by the immunoproteasome in cells of the immune system, and protein secretion, which is regulated by the Sec61 translocon in the endoplasmic reticulum. Inhibiting these fundamental regulators of disease processes offers an attractive approach to treating many diseases, providing much-needed hope to those with autoimmune diseases and cancer.
Playing a critical role in the body's immune system, the immunoproteasome is abundantly expressed in immune cells and acts as a master regulator of cellular function by degrading intracellular proteins.
Selective inhibition of the immunoproteasome with KZR-616 has the potential to reduce inflammation by targeting dysfunctional immune cells involved in autoimmunity – , such as T -cells and B -cells – , without causing widespread immunosuppression in patients.
In doing so, KZR-616 has the potential to affect multiple drivers of immune-mediated diseases and harmonize the body's immune system by restoring the immune response.
The Sec61 translocon’s activity is a highly conserved process, as virtually all secreted and transmembrane proteins utilize Sec61 to enter the endoplasmic reticulum (ER) and begin the process of transmembrane presentation (beginning of the protein secretion pathway). Each protein expresses a unique signal sequence or transmembrane domain. By blocking the functional interaction of signal sequences and Sec61, our tool compounds can inhibit the expression of a selected protein or proteins.
Inhibiting the protein secretion pathway where it begins via the Sec61 translocon represents a novel therapeutic target for blocking expression of therapeutically relevant targets such as cytokines, oncogenic receptors and immune checkpoint molecules. Previously described inhibitors of Sec61 have shown anti-tumor activity but lacked adequate pharmaceutical properties or tolerability for clinical development. Kezar has succeeded in generating potent Sec61 inhibitors with improved tolerability and drug-like physicochemical properties and small molecules that selectively target discrete or select groups of therapeutically relevant proteins. Our first-in-class Sec61 inhibitors, such as our first clinical candidate, KZR-261, have shown broad anti-cancer activity against multiple tumor types in vitro and in vivo.