Early-phase Discovery Research Articles

Conference Scene: Cell and Gene Therapies: Clinical and Near-Clinical Focus

The Phacilitate Cell and Gene Therapy Forum was a showcase of the steps required for translational medicine. The major focus was on requirements from early phase discovery through to the regulatory and business processes to bring treatments to patients. Talks on discovery and new methodologies and technologies were presented in light of adaptability to treatment regimens. Venture capitalists and bank representatives, external evaluators of these new treatments, gave valuable financial process insight. US FDA officials offered explanation and advice on successful approaches to the regulatory challenges to this new and emerging field. Completing the picture were talks from contract suppliers and manufacturers of necessary materials and equipment.

Streamlining hit discovery and optimization with a yoctoliter scale DNA reactor

Background: The field of DNA-encoded technology offers a cutting edge approach to creating 109 – 1012-size small molecule libraries for the rapid identification of drug-like hits. The YoctoReactor® (yR) is the newest DNA-encoded technology and features an innovative and fundamentally different design. Objective: This technology evaluation presents the basic principles of the yR drug discovery technology platform and discusses its potential as an alternative to current hit discovery methods where high quality and selective drug-like hits can be delivered together with instant structure activity relationships (SAR). Conclusion: The yR controls and encodes billions of different synthesis combinatorially through self-assembly of DNA into three-dimensional DNA junctions. The center of these junctions forms a yoctoliter (10-24 L) volume reactor where single-molecule, DNA- encoded reactions can take place. yR technology circumvents the high throughput screening process (HTS). Instead, drug-like families of hits are rapidly identified by molecular evolution in a single tube approach making it highly parallelizable and scalable. DNA-encoded technologies such as the yR, therefore, represent a solution to many of the bottlenecks in current early phase discovery and in handling the vast emerging opportunities in functional genomics, systems biology and proteomics.

Integration of mass spectrometry into early-phase discovery and development of central nervous system agents.

The early-phase discovery and development of useful central nervous system (CNS) agents present ample opportunities to exploit mass spectrometry and provide detailed compound/mixture characterization, or to make the process faster and/or more economic. Neuropeptide FF antagonists and centrally active thyrotropin-releasing hormone analogues were used as specific examples in this work. We evaluated the characterization of focused libraries of peptide derivatives by electrospray ionization, tandem mass spectrometry and liquid chromatography/tandem mass spectrometry on a quadrupole ion trap and nanoelectrospray on a Fourier transform ion cyclotron resonance mass spectrometer. Immobilized artificial-membrane chromatography was employed as a model to predict/rank new agents against lead compounds for their potential to reach the central nervous system in pharmacologically significant amounts. Measuring brain concentrations in rodents after the intravenous administration of test compounds was used as an in vivo approach, and we took advantage of microdialysis sampling that furnished samples without interfering tissue matrix and afforded the estimation of extracellular concentrations in a localized part of the brain. Overall, making atmospheric-pressure ionization mass spectrometry an integral part of the process has played a major role in increasing throughput, selectivity, specificity and detection sensitivity and thereby providing useful information about the extent or mechanism of transport and metabolic activation/inactivation in early-phase discovery and development of CNS agents.