Repositioning HIV-1 integrase inhibitors for cancer therapeutics: 1,6-naphthyridine-7-carboxamide as a promising scaffold with drug-like properties.

Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L-870,810 with goals to (1) improve upon limitations of naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]naphthyridines were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]naphthyridines with structural variation on 7-carboxamide delivered novel compounds with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.

Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cells.

The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, is a critical regulator of signaling in T cells and recently emerged as a candidate target for therapy of autoimmune diseases. Here, by library screening, we identified a series of noncompetitive inhibitors of LYP that showed activity in primary T cells. Kinetic analysis confirmed that binding of the compounds to the phosphatase is nonmutually exclusive with respect to a known bidentate competitive inhibitor. The mechanism of action of the lead inhibitor compound 4e was studied by a combination of hydrogen/deuterium-exchange mass spectrometry and molecular modeling. The results suggest that the inhibitor interacts critically with a hydrophobic patch located outside the active site of the phosphatase. Targeting of secondary allosteric sites is viewed as a promising yet unexplored approach to develop pharmacological inhibitors of protein tyrosine phosphatases. Our novel scaffold could be a starting point to attempt development of "nonactive site" anti-LYP pharmacological agents.

Discovery of novel small-molecule inhibitors of human epidermal growth factor receptor-2: combined ligand and target-based approach.

Consensus virtual screening models were generated and validated utilizing a set of known human epidermal growth factor receptor-2 (HER2) inhibitors and modeled HER2 active and inactive state structures. The virtual screening models were successfully employed to discover a set of structurally diverse compounds with growth inhibitory activity against HER2-overexpressing SKBR3 breast cancer cell line. A search of a 3D database containing 350000 small-molecules using the consensus models retrieved 531 potential hits. Of the 531 hits, 57 were selected for testing in SKBR3 cells on the basis of structural novelty and desirable drug-like properties. Seven compounds inhibited growth of SKBR3 cells with IC50 values <10 microM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.