Selection Guidelines for Small Molecule Structures for Screening

Structures are generally selected for screening based on their ability to add diversity to the NCI small molecule compound collection. The submission of novel heterocyclic ring systems is particularly encouraged. In addition, the submission of compounds with drug-like properties utilizing the concept of privileged scaffolds ^1,3 or structures based on computer-aided design is encouraged. The program is not intended to handle extensive supplier SAR studies which include large numbers of similar analogs. If analogs within a series are to be submitted it is recommended that suppliers initially pre-select only the compounds within an analog series which will most efficiently provide the greatest information. This will insure the structures which are of most interest to the supplier are selected. If initial submissions show activity, they can provide a basis for consideration of future analogs. Highly flexible acyclic analogs with accompanying entropic liabilities or without prior activity data are generally not accepted. Submission of structures containing problematic linkages or functional groups for successful drug development (e.g. nitro, nitroso, -N-N-, -N=N-, imine, semicarbazone,thioamides, thioureas) are discouraged. Analogs related to well-studied agents (e.g. brefeldins, anthracyclins, taxanes, camptothecins, combretastatin, aminoacridines, platinum-based agents) which have been the subject of thorough SAR investigations are also generally not selected without providing a rationale, or preferably data, for improved or novel biological or chemical properties which would support continuing development. As a service, the program also supports NCI 60 cell screen characterization (e.g. tumor selectivitiy, COMPARE data) of important individual late pre-clinical or investigational clinical agents.

Pan-assay interference compounds (PAINS) whose activity does not generally depend on a specific, drug-like interaction between molecule and protein are also discouraged. A list of the most notorious PAINS is below but PAINS are not limited to these chemotypes.⁴

• Toxoflavins
• Isothiazolones
• Curcumin analogs
• Hydroxyphenyl hydrazones
• Ene-rhodanines
• Phenol-sulfonamides
• Enones
• Quinones
• Catechols

The following classes of materials are generally not accepted:

• Radicals
• High MW pegylated or similarly derivatized agents
• Multiple pharmacophores linked by a tether(s)
• Physical mixtures of active components
• Reactive molecules, thermal or photo labile molecules (e.g. mustards, acyl halides, α-halo carbonyl compounds, reactive Michael acceptors)
• Nanoparticle formulations

1. Evans, BE; et al.; Methods for Drug Discovery: Development of Potent, Selective, Orally Effective Cholecystokinin Antagonists, J. Med. Chem., 1988, 31 2235-46.
2. Review: Horton, DA; Bourne, GT; Smythe, ML; The Combinatorial Synthesis of Bicyclic Privileged Structures of Privileged Substructures. Chem. Rev. 2003 103, 893-930.
3. Welsch, ME., Snyder, SA., Stockwell, BR.; Privileged scaffolds for library design and drug discovery. Current Opinion in Chemical Biology 2010, 14:347-361
4. Comment: Baell, J, Walters, MA; Chemistry: Chemical con artists foil drug discovery. Nature, 2014, 513, 481-483. (http://www.nature.com/news/chemistry-chemical-con-artists-foil-drug-discovery-1.15991)