New platform set to accelerate early-stage targeted protein degradation

Sygnature Discovery, the global integrated drug discovery company, has unveiled a new platform that facilitates the combinational high-throughput assembly and review of molecular degraders (CHARMED), in response to a sustained rise in demand for its multi-disciplinary expertise.

What is the CHARMED platform?

Developed in-house at Sygnature Discovery, CHARMED is a technology platform designed to accelerate and support early-stage targeted protein degradation (TPD) programmes.

It offers combined high-throughput chemistry, in vitro biology and DMPK assays, as well as access to ‘Ready-to-Couple’ 96-well plates that capitalise on diverse linkers and popular ligase warheads, delivering rapid synthesis, screening, and characterisation of bifunctional degraders to speed up the identification of lead compounds for novel targets.

Dr Simon Hirst, founder and CEO of Sygnature Discovery, says: “The CHARMED platform combines our world-class, in-house expertise across chemistry, in vitro biology, and DMPK with a practical toolkit that helps clients to expedite their drug discovery.

Benefits of CHARMED

“Across the industry, we are seeing a significant amount of interest in targeted protein degradation, but a lot of organisations are struggling to find either start points in their programmes, or molecules that have the right properties to succeed in the clinic.

 “One of the key challenges with targeted protein degradation and bi-functional molecules is that their physical properties are unusual and outside of the ‘rule of five’, and as such, we need to develop technologies to assess these properties and filter them to allow us to select the molecules with the best outcomes.”

“In the CHARMED platform, we bring together a number of technologies at Sygnature, combining our high throughput chemistry capabilities with high throughput biology,” Simon explains, “We are supporting the rapid synthesis of bi-functional molecules with a series of assays and platforms that will assess their potential to go forward.”

Dr Roland Hjerpe is Senior Principal Scientist, Bioscience at Sygnature Discovery and leads the targeted protein degradation work. He says: “In most cases, targeted protein degradation relies on bringing a ubiquitin ligase into close proximity with a target protein. As such, this modality does not rely on the target protein having a well-defined and accessible active site or functional binding pocket. This means that affinity screening methods based on affinity selection mass spectrometry (ASMS) or DNA-encoded libraries (DEL) can be used to identify ligands that may bind to any available pocket on the target protein. But not all proteins are the same, and not all protein targets are easily degraded.

“This is where CHARMED comes in – allowing organisations to rapidly assess the feasibility of a degrader project for their protein of interest using two of the most common ligases, thus accelerating and de-risking their project, and cutting time and costs. The platform provides a quick way to collect data and triage a large number of molecules into a smaller set. Not only this, but Sygnature Discovery offers interpretation of the data, and the relevant, integrated expertise required to fast-track projects.”

What Sygnature Discovery can offer

Dr Simon Hirst adds: “Whilst some organisations still divide up the different stages of the drug discovery journey to CROs across the world, we feel a more integrated approach is demonstrably better. Our experienced scientists become part of the project’s discovery team, solving problems, and driving projects forward. We have a proven track record of delivering over 21 clinical candidates, meaning we have the experience to truly make a difference and give projects the best chance of success. Indeed, our co-located teams of drug hunters at Sygnature Discovery provide an integrated offering that can take a project all the way from target identification to an investigational new drug (IND) candidate.”

CHARMED provides parallel synthesis of bifunctional PROTAC degrader compounds; an in-stock collection of novel linkers and ligase ligands for lead optimisation, HTRF^®, AlphaLISA^® or Jess-system degrader assays for endogenous targets; engineered live-cell kinetic degradation assays, and high throughput in vitro ADME assessment.