Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK).

Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3.

Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide.

A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.

Associations of estradiol and testosterone with serum phosphorus in older men: the Osteoporotic Fractures in Men study.

Postmenopausal women consistently have higher phosphorus levels than similarly aged men. As it is known that estradiol induces phosphaturia in rodents, we evaluated the cross-sectional association of sex hormones with serum phosphorus in 1346 community-living older men (mean age 76) of which 18% had moderate (stage 3) kidney disease. Using linear regression with serum phosphorus levels as the dependent variable, we found that for each 10 pg/ml higher total estradiol level there was a statistically significant 0.

Serum phosphorus levels and the spectrum of ankle-brachial index in older men: the Osteoporotic Fractures in Men (MrOS) study.

A higher serum phosphorus level is associated with cardiovascular disease (CVD) events among community-living populations. Mechanisms are unknown. The ankle-brachial index (ABI) provides information on both atherosclerosis and arterial stiffness.

Dihydroxylphenyl amides as inhibitors of the Hsp90 molecular chaperone.

Information from X-ray crystal structures were used to optimize the potency of a HTS hit in a Hsp90 competitive binding assay. A class of novel and potent small molecule Hsp90 inhibitors were thereby identified. Enantio-pure compounds 31 and 33 were potent in PGA-based competitive binding assay and inhibited proliferation of various human cancer cell lines in vitro, with IC(50) values averaging 20 nM.

Structure activity relationships of quinoline-containing c-Met inhibitors.

A series of quinoline-containing c-Met inhibitors were prepared and studied. Chemistry was developed to introduce a pyridyl moiety onto the 2-aryl ring present in a lead molecule which mitigated the potential for quinone formation relative to the original compound. The study also assessed the importance of an acylthiourea moiety present in the lead structure for effective binding to the c-Met protein ATP site.

Design, synthesis, and biological evaluation of novel human 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) substrates.

The structure-based design, chemical synthesis, and biological evaluation of novel MTAP substrates are described. These compounds incorporate various C5'-moieties and are shown to have different k(cat)/K(m) values compared with the natural MTAP substrate (MTA).

Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics.

The enzyme 17beta-hydroxysteroid dehydrogenase type 10 (HSD10), also known as amyloid beta-peptide-binding alcohol dehydrogenase (ABAD), has been implicated in the development of Alzheimer's disease. This protein, a member of the short-chain dehydrogenase/reductase family of enzymes, has been shown to bind beta-amyloid and to participate in beta-amyloid neurotoxicity. We have determined the crystal structure of human ABAD/HSD10 complexed with NAD(+) and an inhibitory small molecule.