Molecular Targets Program

The MTP is interested in collaborating with external groups to acquire broader chemical diversity for screening in our high throughput screens.  Please consult our guidelines for information on the types of samples that are of interest to the MTP.

Guidelines for MTP Chemical Libraries 

1.0       Desired samples            

The Molecular Targets Program (MTP) maintains a large chemical library of pure compounds and natural product extracts for screening in high throughput assays related to cancer and viral disease.  Our mission includes discovery of both drug leads and chemical probes. We welcome samples from collaborators which increase the chemical diversity of our screening collection.  Our focus is on natural products and natural product-like synthetic compounds. We generally do not purchase screening samples; instead, we rely on collaborations where testing data is traded for access to screening samples.  

            1.1       Pure Compounds            

We are most interested in chemical diversity from natural sources and from diversity-oriented synthesis.  Positive features include chirality, extensive functionalization, and lack of reactivity.  Planar, aromatic combinatorial libraries are not of interest, nor are compounds with reactive functional groups.  Compounds need not conform to Lipinski’s rules of five, however polyphenolics and other “nuisance” compounds are not desired.              

            1.2       Extracts            

Current areas of interest include extracts of high altitude plants, unusual fungi, central Asian plants, temperate marine invertebrates, and plants used as spices or condiments.  We are not interested in extracts which duplicate current holdings, which are strong in tropical plants and Pacific marine invertebrates.  Our current preference is to process 100-200 mg amounts of extract through a prefractionation process, generating multiple samples per parent extract.  These fractions are used for screening.

2.0       Mechanism for collaboration            

The MTL prefers to work with library source organizations under a formal Material Transfer Agreement (MTA) which defines the rights and responsibilities of the MTL and the source organization.  A draft agreement is generally modified to fit specific needs of both organizations.  The NCI Technology Transfer Center (http://ttc.nci.nih.gov/) assists in developing MTAs and other agreements. 

3.0       Desired sample data 

            3.1       Pure Compounds            

We require the chemical structure of all submitted compounds be supplied prior to testing.  The structures will be held in confidence.  These structures should be submitted in the sd file format with unique compound identifiers.  Use of laboratory notebook identifiers as primary identifiers is discouraged.  In addition to the sd file, a spreadsheet containing all relevant data is required.  For samples submitted in 2D-bar coded vials or plates, the rack or well locations must be specified completely.  Molecular formulae and molecular weight data are also useful, and while these can be calculated from the structure, adding them to the spreadsheet can serve as an internal check of the correctness of the structure.  Compounds should be at least 90% pure, as judged by NMR, HPLC, or other methods.  We do not require detailed QC data to be supplied to us prior to screening, nor will we routinely conduct QC studies of screening compounds.            

            3.2       Extracts            

Source taxonomy is requested.  In some cases (microbes) this may not initially be feasible, but for most samples it is enormously helpful in prioritizing extracts for bioassay-guided fractionation. 

4.0       Desired sample format and amount            

Our most favored sample format is 1.4 mL 2D bar coded polypropylene tubes in 96-position racks (preferably Micronic).  It is usually most convenient to ship the samples dry.  Either 0.5 mg or 1.0 mg amounts are sufficient for screening purposes.  We would prefer that source organizations not ship larger amounts of screening compounds.  Less favored formats are ordinary polypropylene or glass vials, 96-well plated compounds, and non-bar coded tubes.  Bar codes should be used to identify samples if at all possible with any format. For extracts, our prefractionation process requires 100-200 mg of extract, depending on type of extract.  If prefractionation is not to be done, 5.0 mg of extract is sufficient for obtaining primary screening results. All samples should be accurately weighed prior to shipping, or aliquotted and evaporated from solutions of known concentration. Samples will routinely be dissolved in DMSO after receipt and stored frozen at -20°C. 

5.0       Resupply of pure compounds            

Once active samples are identified in HTS assays and confirmed, it is our practice to request a fresh sample from the supplier for dose-response studies, secondary in vitro screening, and confirmation of sample identity and integrity.  Given that hit rates for most of our HTS assays are less than 1%, it is our experience that most source libraries do not provide hits in all assays.  Nonetheless providers should have a plan for resupplying active samples and should verify the quality of the sample at the time of resupply.

6.0       Analog synthesis            

At the same time as resupply of hits is requested for synthetic compounds, we often request any structurally related compounds the provider may possess, in order to develop structure-activity relationships around the hit.  Note that we do not have an efficient means of funding analog synthesis at this time, although NIH grant supplements can serve this purpose. 

7.0       Coordination with NCI collaborators            

All assays run by the MTP are developed in collaboration with one or more NCI Intramural Principal Investigators (PI).  The PI is generally an expert in the biology which the assay attempts to address, and is usually heavily involved in secondary evaluation of initial hit samples.  The PI is almost always involved in patent filings and publications as a collaborator, co-inventor, and co-author.

8.0       Publications and Patents            

For those active compounds that survive secondary evaluation and are judged of sufficient biological interest, patents and/or publications are likely.  Scientists from the source organization will be included in inventorship and authorship. This is more fully detailed in the MTA.

9.0       Data return to source organization            

Suppliers will be notified of confirmed hits as they emerge from the screening campaign.  In addition, full testing data for all supplier compounds will be communicated to the supplier on a semi-annual basis.  Each set of assay results will include contextual information about the nature of the screening assay, criteria for hits, and biological relevance. We typically run three or four HTS campaigns per year.  Every supplier library may not be run in every HTS assay due to assay cost considerations or assay robustness issues.  It is helpful to have a single designated point of contact at the supplier organization for communication about hits, resupply and data return.

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