The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of

Resistance to antibiotics is currently a major health concern in treating infectious diseases. The most common mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamases, which destroy beta-lactam antibiotics before they reach the bacterial target. Combination therapy, which involves treatment with a beta-lactam antibiotic and a beta-lactamase inhibitor, has been successfully used to control resistance during last two decades. Due to the lack of effectiveness of the currently available beta-lactamase inhibitors against class C enzymes and new variants of beta-lactamases, there is a need to develop an inhibitor with broad-spectrum activity. Since the discovery of clavulanic acid, there has been an enormous research effort in this area to identify better antibiotic/inhibitor combinations and to understand the molecular bases for interactions between beta-lactam antibiotics, beta-lactamases, and beta-lactamase inhibitors. This review describes some of the structure- and mechanism-based approaches to design of new beta-lactamase inhibitors and the study of probable mechanisms of inhibition using X-ray, electrospray ionization mass spectrometry, and molecular modeling techniques.

Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.

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