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Southern Research Institute

Southern Research is a not-for-profit research organization that has been in operation since the 1940s. John A. Secrist III, PhD, is the president and CEO. The institute consists of three divisions: Engineering (Vice President Michael Johns), Drug Development (Vice President Andrew Penman, PhD), and Drug Discovery (Vice President Mark J. Suto, PhD).

The institute is focused on the development of therapies for infectious diseases, CNS diseases (including CNS tumors), and oncology. The cancer research programs in the two life sciences divisions at Southern Research have resulted in the discovery and patenting of five FDA-approved anticancer drugs (lomustine, carmustine, dacarbazine, fludarabine, and clofarabine) and one cytoprotective agent (Ethyol) that reduces toxicities associated with cancer chemotherapy and radiotherapy. The Institute discovered these therapies and developed them through NCI-supported research and by collaborating with various pharmaceutical companies. There are additional compounds in development that originated from Southern Research. Clofarabine is a good example of a long-term lead optimization program at Southern Research that ultimately led to a drug. Clofarabine (Clolar^®) is marketed by Genzyme for pediatric leukemia, and is currently being examined in clinical trials for various other indications, with adult AML being the most advanced of those indications. 4’-Thio-Ara-C, mitopterin, isophosphoramide mustard, and PDX (pralatrexate, discovered/developed jointly among Southern Research, Memorial Sloan Kettering Cancer Center and SRI International), represent other well-known examples of Southern Research’s success in cancer research. In addition, scientists at Southern Research have also evaluated approximately 50% of all FDA-approved cancer drugs currently available for patients in various studies.

The Southern Research Comprehensive Biological Center has the capabilities to identify and develop oncology drug targets (molecular, phenotypic, and pathway), develop assays, identify and optimize hits to generate candidate molecules, generate ligandbound molecular targets, and produce the preclinical data (PK and toxicology) to progress compounds to IND applications. Southern Research has extensive experience in chemical lead optimization programs leading to chemical probes for biological systems, development candidates, and drugs on the market. The Southern Research Comprehensive Biological Center has all of the capabilities to deliver on tasks from target identification, assay development, hit identification including high throughput and “focused” screening, lead optimization, target structural studies, PK/ADME, and animal models for both safety and toxicology. We can support scaleup for animal studies and conduct early formulation work. We have a close relationship with companies for more extensive formulation work. The capabilities include both experimental work as well as predictive computational studies. We use a team approach over all of these disciplines, and our success—as measured in drugs brought to the clinic and to the marketplace—is testimony to the success of this approach. Our teams have been both internal, where we have integrated chemistry and biology successfully to find clinical candidates, and external with both commercial and academic entities.

Target Discovery, Validation, and Progression: Southern Research has a number of internal oncology drug discovery projects. These projects have led to the development of specific cellular and in vivo assays such as in radiosensitization, angiogenesis, and cellular signaling. We also collaborate with the Comprehensive Cancer Center at the University of Alabama and other organizations to develop oncology targets.

The research focus of these laboratories provides many points for interactions with the NCI programs and could provide targets and/or development compounds to the Consortium. Furthermore, the oncology expertise resident in Southern Research will contribute to other CBC programs.

Hit Identification, Characterization, and Optimization: Southern Research uses an integrated hit identification strategy. This includes not only HTS but also medium throughput screening of smaller focused or targeted sets of compounds based upon knowledge of the target, in silico (virtual) screening, and structure- and mechanism-based drug design.

Compound Collection: The Southern Research HTS Center currently stores and manages over 600K compounds (one 300K library, three non-overlapping 100K libraries, and several smaller libraries ranging in size from several hundred compounds to 28K). We have focused sets (for example, a protein kinase targeted set) as well as pharmacophore-based sets (such as a 3K nucleoside analog set and a natural product set). These smaller, focused libraries total approximately 32K compounds. The three 100K libraries each have smaller (3K-10K) diversity subsets. The 100K sets were selected for scaffold diversity and cluster size (using the software packages SYBYL, Pipeline Pilot, and LeadScope), as well as filtering for chemical and relevant physical properties, including reactivity, hydrophilicity, and other known biological activities that suggest that the compounds would be good drug candidates. The various sets of compounds are stored and managed in 384-well plates. In addition, Southern Research also has a solid compound repository of more than 35K compounds.

High Throughput Screening Center: Since 2000, Southern Research has invested millions of dollars in a state-of-the-art HTS Center. The Center has capabilities to screen in a wide variety of cell-based and protein-based formats including high content cellular assays (using the Evotec Opera, Luminex and Meso Scale Discovery systems). It possesses the logistics to maintain and rapidly screen 1,000,000 compounds or more per campaign and to confirm hits with counter screens and in silico techniques. The compound management capabilities allow Southern Research to easily import hundreds of thousands of compounds from other organizations and place them into screening assays. Our system allows us to track and limit access to proprietary compounds and thus maintain IP rights for suppliers. Furthermore, collaboration with the other biochemistry and cell biology groups allows the confirmation of compound mechanism of action and progression of compounds through secondary assays. The Center is a suite of laboratories designed for efficient screening of large compound libraries while maintaining the capacity for a wide variety of assay types. The staff within the HTS Center has in-depth experience and a demonstrated proficiency in transferring bench top assays to the robotics platform and executing cell-based and biochemical screens.

Our primary data management system is IDBS’ ActivityBase7, which writes to our Oracle 10g database; we also use the LIMS system. For most of our compound related exports, ActivityBase is coupled with Accelrys’ Pipeline Pilot. Pipeline Pilot allows users to create a useful workflow and also allows for additional user generated components. Compound data stored in our system can be queried and exported in a variety of formats. SD files are the most common format used to transfer structural data; however we are capable and accustomed to working with our collaborators to identify other suitable formats (delimited text, Excel files, etc.) where applicable.

Medicinal, Structural and Computational Chemistry: The Organic Chemistry Department currently has a large staff of senior chemists, bench-level synthetic chemists, chemistry support personnel, structural chemists, and computational chemists. Our approaches to hit characterization and optimization vary depending upon the nature of the screen, the quality of the data, and background knowledge of the particular hit including the cluster size (number of related compounds that are active). Typically, minimal characterization of confirmed hits would include mass spectrometric, NMR spectroscopy, and HPLC analysis, and comparison with a freshly purchased or prepared sample. Resynthesis is the definitive confirmation of hit structure. Once a decision is made to consider chemical optimization, we employ a team approach, blending bioinformatics, computational chemistry, structural biology, and iterative synthesis to systematically identify the structural features of the molecule that contribute to activity. Synthetic target compounds and libraries for follow-up screening are selected by cluster analysis (Distill in SYBYL, ChemTree, Pipeline Pilot, LeadScope), and common structural elements among the actives are identified and their relevance to activity evaluated using various criteria known to increase the likelihood of relevant biological activities. Privileged scaffold cluster members as well as active singletons are aligned to maximize the overlap of such atom groups to develop pharmacophore model(s) through the application of software tools such as Discotech, Galahad (SYBYL), and Search/Compare (InsightII). Analog searches include substructure and similarity-based methods as well as pharmacophore-based 3D searches of available compound databases. To facilitate database searches we have generated in-house 3D databases totaling approximately 3.4 million commercially available compounds, complementing Zinc and other public databases. Where experimentally derived protein structures of screening targets are available for screening targets, X-ray/NMR structures of the target and its ligandbinding pocket are evaluated, along with other targets amenable to homology modeling. In such cases, we perform docking and scoring predictions using Glide, Autodock, Gold, and LigandFit, and multiple scoring functions are employed to evaluate predicted ligand binding. The computational group also conducts virtual screening, virtual toxicology, and QSAR.

Thus, proposed synthetic targets will have been analyzed for a variety of relevant physical properties, such as drug-like properties (as one measure of biological relevance), reactivity, hydrophilicity, other known biological activities, and, in the case of second generation libraries, overall chemical diversity of the new compounds within the structural context of the identified hit and previously screened agents. Later in the optimization process, prodrug strategies will be employed if appropriate, and we will always remain mindful of pharmacokinetic, metabolic, and other issues that may redirect the synthetic program. A laboratory dedicated to large-scale (up to hundreds of grams) synthesis of intermediates and final targets is also available.

PK/ADME: To more efficiently select chemical series for further optimization, Southern Research has implemented a rapid PK program (“PK-kwik”) to select compounds with the most desirable PK properties early in the design cycle. The center has extensive experience in all of the preclinical studies required to file an IND. These include ADME/DMPK, toxicology, bioanalysis, and animal and cellular efficacy models for oncology. In addition, the center uses in silico models to predict the “developability” of compounds. The center currently utilizes several software packages such as the ADMET Collection in Pipeline Pilot, Discovery Studio, QikProp in Schrödinger, and VolSurf as implemented within SYBYL. The ADMET Collection provides capabilities to predict many properties, including aqueous solubility, human intestinal absorption, blood-brain barrier penetration, plasma protein binding, cytochrome P450 2D6 inhibition, and hepatotoxicity. The QikProp module of Schrödinger provides additional predictive capabilities, including aqueous solubility, Caco-2 Cell permeability, human oral absorption, blood-brain barrier permeability, skin permeability, serum albumin binding, and hERG inhibition. The ADMET models included in VolSurf cover aqueous and water-DMSO solubility, Caco2 permeation, blood-brain barrier permeability, biopharmaceutical classification, protein binding, volume of distribution, hERG inhibition, and CYP3A4 metabolic stability. Other modeling packages provide additional functionality. We recognize the limitations of software models and, where possible, employ multiple algorithms to compare predictions.

The small animal imaging facility at Southern Research will contribute to the Cancer Imaging Program to both facilitate progression of compounds through animal studies as well as provide the potential for the translation of these technologies to human clinical trials and FDA approval. The center also provides bioanalysis data for samples from clinical studies.

Southern Research’s Information Technology System Support Group: Our Information Systems department is a centralized group that provides a wealth of experience to support the computational, data storage, and transfer needs of Southern Research Institute. The group has technical expertise in network support, database administration, ERP, security, 21 CFR Part 11 compliance, validation, and document management/control.