Discovering Novel Biology on an Unprecedented Scale
Our proprietary gene trapping and gene targeting technologies enable us to explore gene function in the mammalian genome on an unprecedented scale.  Using these technologies, we are generating 5,000 knockout mouse lines whose DNA has been modified to disrupt, or “knock out”, the function of a single gene.  Because there is a close similarity in gene function and physiology between mice and humans, with approximately 99% of all human genes having a counterpart in the mouse genome, knockout mouse technology has proven fundamental to our understanding of biology and medicine.  Notably, the application of this technology has been so useful in the area of biomedicine that it was recognized in 2007 with the Nobel Prize in Medicine.  

Drug Target Identification
Each knockout mouse in the Genome5000^TM program undergoes comprehensive phenotypic studies using a battery of advanced medical tests that are specifically adapted for mice.  These evaluative technologies allow us to discover in vivo (within a living organism) the physiological and behavioral consequences that result from the loss or inactivation of a specific gene.  We use this information to assess whether or not the affected gene may be important for human health and would, therefore, be a useful target for potential drug therapies.

Identifying Small Molecule Drug Candidates
For those in vivo-validated drug targets with high pharmaceutical potential, we engage in programs for the discovery of promising small molecule, antibody and protein drugs.  Using established, extensive internal medicinal chemistry capabilities that utilize “Click chemistry,” a set of powerful and reliable tools for the rapid synthesis of novel compounds that was derived from the Nobel Prize winning research of Barry Sharpless, we have generated a sophisticated library of small molecule chemical compounds with drug-like characteristics, which we use in our drug discovery efforts.  Using high-throughput screening assays, we identify "hits," or chemical compounds that demonstrate activity against our in vivo-validated drug targets, and then employ medicinal chemistry efforts to optimize these hits and identify lead compounds that may ultimately enter clinical development.  All of Lexicon's small molecule drug candidates in human clinical trials have been discovered and developed by our internal medicinal chemistry team.

Identifying Antibody and Protein Drug Candidates
In addition to our medicinal chemistry capabilities, we have also established substantial internal antibody and protein drug discovery capabilities.  We use protein expansion and antibody technologies to generate and optimize molecules with appropriate characteristics for drug development.  When possible, we use knockout mice that lack the target protein as part of our antibody discovery platform.  By immunizing these knockouts with the protein they have been engineered to lack, a more robust antibody response can usually be obtained because the knockout’s immune system often responds to the target protein as completely foreign.

Preclinical and Clinical Development
We have established extensive internal capabilities to characterize the absorption, distribution, metabolism, and excretion (ADME) of our potential drug candidates, and evaluate their safety in mammalian models in preparation for preclinical and clinical development.  In all of our drug discovery programs, we use the same technology platform to analyze the in vivo activity and safety profiles of drug candidates in mice as we use in our gene function discovery efforts.  In fact, the knockout mouse serves as an important guide in determining the on-target activity of our lead molecules.

Once we identify a potential drug candidate, we initiate formal preclinical development studies in preparation for regulatory filings with the U.S. Food and Drug Administration (FDA) or international regulatory agencies for the commencement of human clinical trials.  We have established internal expertise in preclinical and clinical development, including clinical trial design, study implementation, oversight, and regulatory affairs.