How Curve’s Proprietary Microcycle® Discovery Platform is Reinventing Drug Discovery
Curve Perspectives article – Ali Tavassoli
With its powerful Microcycle platform technology, Curve Therapeutics is building a pipeline of innovative drugs with a focus on cancer, immunology and inflammation. Our Co-Founder and Chief Scientific Officer, Ali Tavassoli, explains more.
Simon Kerry and I co-founded Curve in 2019 with a vision to transform the lives of patients by developing innovative ways to treat challenging diseases. Our drug discovery platform at Curve builds on 18 years of research from my lab at the University of Southampton.
Curve’s technology is based around our proprietary, gene encoded Microcycle screening platform, which enables the enrichment of active molecules from libraries of Microcycles on the basis of biological function inside a live mammalian cell. The active Microcycles are used as the starting template for the development of drugs which can address high priority disease targets.
The advantage of our platform is that we screen for biological activity inside a mammalian cell, where the target protein is conformationally dynamic, with disease-relevant post-translational modifications. This means that we can conduct activity-based screens with cryptic and allosteric pockets being available to the ligands. Macrocyclic peptide display and DNA encoded libraries only identify hits based on their affinity to a purified, immobilized target in biochemical buffer, which does not always equate to function in a cellular environment.
A privileged molecular scaffold, Microcycles occupy a distinct chemical space. The small size and rigid structure of Microcycles uniquely generates a clear path to a cyclic peptide or small molecule drug.
We are also working on a droplet microfluidic system to allow high efficiency functional screening of Microcycles within a single femtolitre liquid droplet to identify functional hits against membrane proteins and non-protein targets such as RNA.
Our US$1.7 billion global research collaboration with MSD (trade name of Merck & Co., Inc., Kenilworth, NJ USA) attests to the uniqueness of this technology. The agreement was signed in January 2022 to utilize our technology to discover and validate modulators of up to five undisclosed therapeutic targets.
We are initially deploying this approach to build a pipeline of first-in-class small molecule drugs against high-priority cancer, immunology and inflammation targets.
It is vitally important that we find new ways to combat cancer – although there has been huge progress in recent years with a range of new therapeutic innovations, there is still an urgent need for improvement in response rates, safety, and efficacy in cancers for which treatments are available.
So far, our Microcycle technology has allowed Curve to build its own pipeline of first-in-class small molecule drugs including a dual inhibitor of hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2) and an inhibitor of ATIC, a protein that catalyzes the final two stages of de novo purine biosynthesis in mammalian cells.
The hypoxia-response pathway is modulated by HIF, which alters the expression of hundreds of genes and plays a critical role in the survival and growth of solid tumors. HIF activation controls multiple cellular processes such as angiogenesis, metabolism, tissue invasion and metastasis, allowing cancer cells to adapt and survive in low oxygen environments. This pathway is often activated in cancer, leading to a poor prognosis for patients. There is only one approved HIF inhibitor (an inhibitor of HIF-2), Merck’s belzutifan, a treatment for von Hippel-Lindau disease-associated renal cell carcinoma), which points to the novel nature of this approach.
A priority target for our pipeline is forkhead box A1 (FOXA1), which is highly expressed in most breast cancers, in some cases making the tumor more aggressive by increasing its response to estrogen. This could lead to another first-in-class drug, as there has been significant interest in the target but no inhibitors identified so far.
There are still cancers where there are limited treatment options, for which prognosis is poor. By discovering innovative ways to target the disease, Curve Therapeutics and its Microcycle technology platform can transform the lives of patients who have run out of options.
