High-throughput screening (HTS) capabilities and informatics tools are central to Calibr’s drug discovery and optimization efforts. Calibr’s advanced automation infrastructure combines state-of-the-art robotics, liquid-handling devices, and an array of signal detection modalities, with sophisticated data analysis platforms, creating a format for scientists to screen diverse collections of compound libraries across a large number of phenotypic cell-based assays. Screening campaigns are initiated with multi-parametric flow cytometry, fluorescence microscopy, and gene expression assays, in addition to standard biochemical and reporter-based assays, and can identify both tool compounds for rapid validation of novel concepts, as well as starting points for drug discovery. These activities are supported by Calibr’s large, diverse chemical libraries (~10^6 compounds) as well as its hit confirmation, SAR by inventory and compound management capabilities. Calibr’s discovery informatics expertise includes software engineering, data processing, quality control, and data analysis, including the reduction of multi-dimensional data to informative single values. Informatics tools are leveraged throughout the drug discovery process, including cheminformatic analysis and molecular modeling to facilitate lead optimization, as well as computational methods for extrapolating PK/PD data into higher species, including prediction of human doses and ADME parameters. In addition, Calibr has developed highly effective biochemical and genomic tools to elucidate the underlying molecular mechanisms of compounds identified in pathway and phenotypic cellular screens.
The medicinal chemistry group at Calibr is engaged across the full spectrum of drug discovery activities – chemists work collaboratively with discovery biology to identify and profile hit compounds from primary screens, rapidly generate structure-activity relationships through inventory and analog synthesis, and ultimately nominate them for intensive lead optimization to improve potency, duration of action, physiochemical, pharmacological, and toxicological properties. The latter activities are carried out in close collaboration with the pharmacology and bioanalytics staff at Calibr. The group carries out the design and synthesis of a variety of drug-like, small heterocyclic compounds and natural product derivatives, as well as peptides, peptidomimetics, and tissue-targeted drug conjugates. Chemists work in project teams that are relatively small and often championed by talented postdoctoral fellows who are responsible for optimizing screen hits to drug candidates. The medicinal chemistry laboratory facilitates all aspects of chemical synthesis, purification, and characterization, and is a key element of the streamlined research environment at Calibr.
The pharmacology and analytical chemistry capabilities at Calibr are integral to the cross-functional model at Calibr for rapidly generating in vivo proof-of-concept studies, starting with the initial profiling of hit compounds through optimization and ultimately to pre-clinical candidate nomination. The expertise of the in vivo pharmacology team spans a wide range of disease areas including oncology, diabetes, cardiovascular, inflammation, and autoimmunity, and thus accommodates the diverse needs of Calibr’s broad preclinical portfolio. Collectively, team members are highly skilled in cardiothoracic, orthopedic, gastrointestinal, reproductive, and neurological surgery and physiology, and have both a comprehensive knowledge of conventional disease models and a focus on innovative model development. The group also routinely performs pharmacokinetic, pharmacodynamic, and exploratory toxicology studies, supporting lead optimization and facilitating key decision points. The analytical chemistry group operates in tandem with in vivo pharmacology to sustain these efforts, enabling critical method development and analysis of pharmacokinetic, toxicokinetic, and stability studies, in addition to in vitro profiling activities that include determination of kinetic and thermodynamic solubility, as well as relevant enzyme inhibition and ion channel modulation.