High Quality Compounds from Novel Chemical Methodologies

The CTCMLD library contains high quality, analytically pure small molecules, which are chemically synthesized using the state-of-the-art chemical methods developed within the CTCMLD. The library members are well characterized for their purity and identity using analytical LC-MS (all compounds) and NMR spectroscopy (>8% of all compounds). All compounds in the library satisfy the purity and solubility standards enforced for compound acceptance by the National Institutes of Health: Molecular Libraries - Small Molecule Repository.

Novel Heterocyclic Molecular Frameworks

The CTCMLD library entirely consists of novel heterocyclic scaffolds that are highly under-represented in the commercial libraries. Computational Tanimoto analyses reveals that only less than 1% of the CTCMLD compounds are considered similar (coefficient of over 0.6) with members of such major commercial libraries as ChemBridge Diverse Sets, ChemDiv, Prestwick and Spectrum libraries. The library members incorporate over 40 different drug-like heterocyclic core structures, including imidazopyridines, tetrahydroindolones, tetrahydroquinolinones, hexahydroacridinones, etc. In addition, over 25% of the compounds in the library structurally resemble a number of bioactive natural products, such as corynanthe alkaloids, cytochalasins and quinolones.

High Level of Chemical Diversity

High chemical and shape diversity represents another key feature of the CTCMLD library. Principal moment of inertia (PMI) analysis indicates that the CTCMLD library has significantly broader distribution in molecular shapes than the ChemBridge and ChemDiv libraries. Additionally, the library members are more 3-D shaped with 44% of sp3-carbons on average, compared to 37% in ChemBridge Diverse Sets and 31% in the ChemDiv library. These structural features enable the library to be especially useful in screens targeting protein-protein interactions, in phenotypic or pathway screens, and in screens against other challenging drug targets.

Optimum Physicochemical Properties

Favorable physicochemical properties of the CTCMLD library ensure the maximum biological relevance of the library compounds. The library features a mean molecular weight of 525, a mean calculated LogP of 4.3, and a mean polar surface area of 88.1 angstroms squared. An average library member has 8.5 rotatable bonds, 0.9 hydrogen-bond donors and 4.8 hydrogen-bond acceptors. All these parameters are well fit within the optimum ranges for drug-like small molecules.

Proven Track Record for Chemotype Discovery

The CTCMLD library has a proven track record of generating quality hits in both cell- and target-based assays. A number of biologically active compounds have been identified by the Kozmin laboratory and by our collaborators. These compounds include an inducer of oxidative stress in cancer cells (Cui et. al., ChemBioChem, 2010, 11, 1224.), three potent inhibitors of glycolysis (Ulanovskaya el. al., Chem. Biol. 2011, 18, 222.; Cui et. al., Proc. Natl. Acad. Sci., 2011, 108, 6763.), two inducers of mitochondrial permeability transition, a mediator of cellular senescence, and multiple activators and enhancers of heat shock response. The structures of three representative pharmacological probes identified from the CTCMLD library are shown below.

In addition, a majority of compounds in the CTCMLD library have been subjected to over 350 different biological assays carried out by the NIH Molecular Libraries: Probes Centers Network (MLPCN). A total of 148 assays have at least one active compound from the CTCMLD library. Over 16% of the compounds in the library have been identified as hits in at least one biological assay. Over 30 compounds have already been confirmed to exhibit the desired activities in both target and cell-based assays, with such disease implications as cancer, infectious diseases and drug additions.

Four representative hit compounds from the MLPCN screens are shown below. They include an antagonist of oxexin 1 receptor as potential treatment of drug addiction, sleep disorder and behavioral plasticity, an inhibitor against Rin1-Abl interaction as potential treatment of Gleevec-resistant chronic myelogenous leukemia (CML), an inhibitor of glutaminase as potential treatment of c-Myc expressing cancers, and an activator of BRCA1 expression as synergistic enhancers of anti-estrogenic agents in breast cancer treatment.