Janssen’s partnership reportedly builds on Evotec’s discovery that small molecules can bind allosterically to certain extracellular receptors and induce a natural proteolytic cleavage process to shed the ectodomain.
“The shedding of the ectodomain of a membrane protein will have a variety of effects dependent on the specific target and the role it plays in normal and disease pathology. For example, the shedding of a protein that is involved in a ligand-driven cellular signaling will lead to a cessation of signaling by that particular pathway,” said a spokesperson for Evotec.
As well as disrupting cell signaling, the process can lead to the shed ectodomain acting as a sink for the native ligand of the targeted receptor. The potential for the approach to unlock first-in-class novel modes of action has attracted Janssen, which agreed to pay Evotec research funding and success-based research and commercial milestones of up to approximately €210m ($215m) per project.
In return, Janssen has gained the chance to jointly conduct screens on the identified targets with Evotec. The partners will collaborate on hit identification and lead optimization of the most promising chemical assets.
The collaboration will use a suite of proprietary assay principles and computational tools, TargetAlloMod, that Evotech has created to screen extracellular receptor targets for the induction of shedding by small molecule allosteric modulators. TargetAlloMod represents a different approach to drug discovery.
“The shedding-based approach to drug discovery is different from conventional approaches to target cell surface receptors such as neutralizing antibodies in that it follows an event-driven paradigm rather than occupancy driven. As such one shedding activator molecule may lead to the shedding of many molecules of its target cell surface protein,” the spokesperson said.
Evotec’s spokesperson declined to say why the TargetAlloMod platforms are a good fit for the Janssen project, explaining that it is one of the company’s “core principles not to comment on partnered projects without prior approval from the respective partner or partners.”