Innovative macrocycle drugs for challenging targets

Macrocycles, new modalities to address challenging biological targets

Polyphor’s peptidic and non-peptidic diverse macrocycles designed to mimic key naturally occurring epitopes and proven to be rapidly optimizable.

Successfully tackling complex biological targets

Our macrocycles sucessfully tackle complex biological targets for which no or only suboptimal solutions have been found.
  • Difficult-to-drug intracellular and extracellular targets (protein-protein interactions, ion channels, GPCRs etc)
  • Challenging selectivity or safety requirements (kinases, ion channels, GPCRs, enzymes, etc.)
  • Oral step-down from approved biopharmaceutical or peptide (life cycle management)
  • New IP in a crowded space (kinase, enzyme inhibitors, etc.)
  • Circumvent lack of SAR diversity to provide alternative, promising scaffolds

Hot spot binding regions of targets of interest

Macrocycles are ideally suited to address contact surface areas of 400 – 2000 Å2 upon binding.
What are macrocycles? Structural features and unique characteristics
Macrocycles are medium-sized molecules combining the capability to bind and modulate the function of difficult-to-drug targets typically tackled with biopharmaceuticals, and the ease of optimization and production associated with small molecule NCEs.


Macrocycles provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure;


They are semi-rigid compounds. They provide a compromise between structural pre-organization and sufficient flexibility to mould to a target surface and maximize binding (induced fit);

Medium-sized macrocycles can interact with larger protein interfaces typical for protein-protein interactions.


Macrocycles can demonstrate drug-like physicochemical and pharmacokinetic properties such as solubility, lipophilicity, metabolic stability, cell permeability and bioavailability beyond the rule of 5.

Polyphor’s macrocycle platform

Our macrocycle library consists of over 50,000 single, untagged, individually purified peptidic and non-peptidic macrocycles readily amenable to all screening formats (binding, enzymatic, cellular, pathway, phenotypical, etc.).

It is a rationally designed, shape-diverse collection of semi-rigid macrocycles. The design is centered around prototypical pharmacophore arrangements mimicking key naturally occurring epitopes typically involved in biological target modulation. Hits from screening the library are typically clustered in families of related compounds already providing a first limited SAR understanding.

This initial advantage is design enabled: We keep exit vector decorations constant across the various scaffolds. We have proven to be able to rapidly optimize macrocycle hit families to leads and beyond with efficient medicinal chemistry driven by structural know-how and highly efficient automated synthesis.

Oral bioavailability and cell penetration of macrocycles

Inspired by nature to adapt conformations to match the polarity of the environment

Very often, penetration of membranes, which is essential for oral bioavailability or intracellular activity, represents a key hurdle for a candidate drug molecule. The unique design of our macrocycles is inspired by nature. Similar to a chameleon and, in molecular terms, similar to Cyclosporine A, Polyphor macrocycles can adapt their conformations to match the polarity of the environment (lipophilic to pass the membrane, hydrophilic to bind to the target).

Cyclosporin A, a natural product, is an inspiring orally bioavailable and cell penetrating peptidic macrocycle adapting its confirmation to the lipophilic membrane – or the polar target (Cyclophillin) environment.

Polyphor macrocycles contain this successful chameleon design principle of Cyclosporin A and thus have a high propensity to be orally bioavailable and cell penetrating. This example of a screening compound from our macrocycle library hides polar functionality in aprotic media and exposes them in protic media, resulting in an oral bioavailablity of 29%.

Improved success metrics for developing preclinical candidates with Polyphor macrocycles

To date we have delivered potent and selective hits (hit families) with a 78% success rate, for which no suitable chemical matter was found prior to testing Polyphor macrocycles. Out of these projects, 39% were successfully progressed through lead optimization.
Fast “holistic” MedChem approach speeds up hit to lead optimization

Polyphor macrocycles are readily assembled in a modular fashion implemented with highly automated synthesis technologies. Rather than addressing MedChem optimization questions (SAR, ADMET etc.) in a stepwise, individual fashion, we address several medicinal chemistry aspects at once and optimize in large library arrays (300-1’000 macrocycles) per optimization round with an average synthesis time of 5-6 weeks per array. This enables a rapid gain of knowledge and structure activity understanding, ultimately shortening hit to lead time considerably and speeding up the overall drug discovery process.

Macrocycle-based drug discovery and development is Polyphor’s competitive edge