The advent of “PROTAC®” molecules, heterobifunctional small molecules that bind at one end to an E3 ligase and at the other end to a protein meant to be degraded for therapeutic effect, has added a new dimension to proteostasis-based therapy. PROTACs have several advantages over simple inhibitors, including catalytic mechanism of action, reduced susceptibility to resistance owing to target mutation, and pharmacologic activity at concentrations lower than those usually needed for simple enzyme effectors. Progenra has developed several novel E3 ligands and utilized them to generate potent PROTAC molecules to degrade multiple therapeutic receptor tyrosine kinases (RTKs) and other targets. We have demonstrated cell proof of concept and are now in the preclinical development stage.
Most of the PROTAC programs in pharma and biotech research organizations operate in a crowded space, employing cereblon or VHL or E3 ligands. PROTAC molecules developed by Progenra from novel E3 ligase ligands are non-cytotoxic and free from the teratogenic potential of cereblon ligase-based PROTACs. Moreover, the novel PROTACs expand the therapeutic potential of the PROTAC class and create new IP.
We are constantly expanding the therapeutic scope of PROTACs by developing additional E3 ligase ligands.
PROTAC Mechanism of Action-
The schematic describes the action of a PROTAC molecule (D) that binds to an E3 ligase on one end and the target protein (T) on the other end. The ubiquitin conjugating enzyme E2 brings charged ubiquitin (U) that is covalently attached to the target protein by E3 ligase. The highly efficient system of the E3 ligase builds a chain of poly-ubiquitin on the target protein. The latter is recognized by the proteasome and the target protein is degraded. The key feature of PROTAC is the efficiency with which single PROTAC molecule is recycled to capture a new target protein.