Ensemble overturns the constraints of customary small molecule drug discovery by finding drug-like properties in novel structures beyond the traditional ‘Rule of 5’. We have successfully and reliably engineered and exploited synthetic beyond ‘Rule of 5’ novel compounds that combine the best attributes of small molecules such as good cell penetration and oral bioavailability with the potency, specificity and slow target off-rates of antibodies.
Our drug discovery platform consists of two components – DNA-programmed chemistry™ used to make libraries of novel small molecules including macrocycles for hit discovery, hit to candidate optimization using conventional synthetic and medicinal chemistry.
Precise Control of Synthetic Chemistry
DNA-programmed chemistry is a patented method that employs DNA to control chemical reactions. Developed by Professor David Liu at Harvard University, DNA-programmed chemistry reactions occur between pairs of chemical building blocks attached to complementary DNA strands. By constructing molecules in a stepwise fashion and cyclizing linear precursors into macrocycles, we have optimized DNA-programmed chemistry to be the most effective way of generating diverse libraries of pure compounds for screening purposes. The high fidelity and selectivity conferred by unique DNA sequences allows millions of compounds to be made simultaneously in the same reaction mixture.
Rapid Identification of Lead Compounds
Ensemble screens libraries of macrocycles for biological activity through rapid, efficient and highly sensitive affinity selection assays. As individual macrocycles have their structure encoded by the attached DNA sequence, DNA amplification by PCR and next generation sequencing permits immediate structure decoding. The identification of active compounds and associated structure-activity relationships (SAR) provides considerable insight into the structures that bind to the disease target.
Individual hit compounds are resynthesized on multi-milligram scale using conventional synthetic methods, and assessed using traditional biophysical and biochemical methods. Following confirmation of functional activity against the disease target, we advance the program using conventional synthetic and medicinal chemistry. The SAR is expanded in the search for more potent and selective compounds, and routine pharmacokinetic assays allow the medicinal chemists to optimize solubility, permeability and metabolic stability. Although the final requirements will vary between targets, our ultimate goal is the discovery of orally active compounds for challenging disease targets, including protein-protein interactions.