Synthesis and pharmacological evaluation of N-(3-(1H-indol-4-yl)-5-(2-methoxyisonicotinoyl)phenyl)methanesulfonamide (LP-261), a potent antimitotic agent.

The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.

Application of a novel [3+2] cycloaddition reaction to prepare substituted imidazoles and their use in the design of potent DFG-out allosteric B-Raf inhibitors.

B-Raf protein kinase, which is a key signaling molecule in the RAS-RAF-MEK-ERK signaling pathway, plays an important role in many cancers. The B-Raf V600E mutation represents the most frequent oncogenic kinase mutation known and is responsible for increased kinase activity in approximately 7% of all human cancers, establishing B-Raf as an important therapeutic target for inhibition. Through the use of an iterative program that utilized a chemocentric approach and a rational structure based design, we have developed novel, potent, and specific DFG-out allosteric inhibitors of B-Raf kinase. Here, we present efficient and versatile chemistry that utilizes a key one pot, [3+2] cycloaddition reaction to obtain highly substituted imidazoles and their application in the design of allosteric B-Raf inhibitors. Inhibitors based on this scaffold display subnanomolar potency and a favorable kinase profile.

Roles for novel pharmacological blockers of aquaporins in the treatment of brain oedema and cancer.

1. Aquaporins (AQPs) are targets for drug discovery for basic research and medicine. Human diseases involving fluid imbalances and oedema are of major concern and involve tissues in which AQPs are expressed. The range of functional properties of AQPs is continuing to expand steadily with ongoing research in the field. 2. Gating domains in AQPs are molecular sites for drug actions. Discovery of the arylsulphonamide AqB013 as an antagonist for AQP1 and AQP4 provided the first pharmacological agent with translational promise for the treatment of diseases in which AQPs have been implicated. The putative binding site for AqB013 in the internal vestibule of the AQP water pore involves amino acid residues that are located in the AQP loop D gating domain. 3. Aquaporins have been proposed as novel targets in cancer and oedema and are associated with a surprising array of important processes in the brain and body, such as angiogenesis, cell migration, development and neuropathological diseases. Functions beyond their simple role as water channels are suggested by the subtype-specific regulation of AQP expression. In both cancer and brain oedema, current therapies are limited and new pharmacological approaches focused on AQPs offer exciting potential for clinical advances.

Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.

Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.