The advent of “PROTAC” therapeutic molecules, bifunctional 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 DUB or E3 inhibitors or activators, 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 is developing a new class of PROTAC molecules that 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, VHL or HDM2 E3 ligases and ligand-based chemistry. Known ligand based PROTAC approaches undertaken by many companies lack novelty and are limited by the ligase captured, the intracellular compartment of the ligase, the mechanism of action, and intellectual property considerations. PROTAC molecules developed by Progenra from novel E3 ligases and ligands are 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. Progenra’s PROTACS hijack novel ubiquitin ligases to ubiquitylate targets affecting immune oncology as well as anti-inflammatory and neurodegeneration cascades.
We hope to expand the therapeutic scope of PROTACs by developing these additional ligases.
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.