The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrange-

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.

The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases regulates multiple biological processes, such as cell proliferation, migration, apoptosis, and differentiation. Various genetic alterations that drive activation of the receptors and the pathway are associated with tumor growth and survival; therefore, the FGFR family represents an attractive therapeutic target for treating cancer. Here, we report the discovery and the pharmacological profiles of 8 (CH5183284/Debio 1347), an orally available and selective inhibitor of FGFR1, FGFR2, and FGFR3. The chemical modifications, which were guided by 3D-modeling analyses of the inhibitor and FGFRs, led to identifying an inhibitor that is selective to FGFR1, FGFR2, and FGFR3. In in vitro studies and xenograft models in mice, 8 shows antitumor activity against cancer cell lines that harbor genetically altered FGFRs. These results support the potential therapeutic use of 8 as a new anticancer agent.

Telomerase activity is detectable in most human tumors but not in most normal somatic cells or tissues. Telomerase inhibition has, therefore, been proposed as a novel and potentially selective strategy for antitumor therapy. In the present study, we found that platinum compounds, including cisplatin [cis-diamminedichloro-platinum (II)], strongly inhibited the activity of partially purified rat telomerase. Telomerase activity can be detected in most human tumors, but not in most normal somatic cells or tissues. 1 The enzyme is a specialized DNA polymerase that directs the extension of telomeric repeats at the 3Ј ends of telomere DNA using its RNA component as a template. [2][3][4] Telomeres are nucleoprotein structures, located at the ends of eukaryotic chromosomes, containing tandem repeats of G-rich hexa-nucleotides (TTAGGG) and complementary strands in human and other vertebrates, ranging from 5 to 15 k base pairs in length. They protect chromosomal DNA from degradation or end-to-end fusion. Since the usual semiconservative replication cannot completely replicate chromosomal ends, normal telomerase-negative somatic cells lose some of their telomeric repeats with each cell division. When sizes lower than a critical length are reached, the cells generally enter senescence or apoptosis due to genomic instability. [5][6][7] To overcome this limitation, most malignant tumor cells express a special enzyme, telomerase, which compensates for the progressive loss in telomeres and secures immortality. Telomerase inhibition has, therefore, been proposed as a novel and potentially selective strategy for antitumor therapy.Currently we are involved in screening for low molecular weight telomerase inhibitors and have found that a number of isothiasolone derivatives strongly inhibit the enzyme in vitro. 8 In the present study, we extended our screening to another group of chemicals and found that platinum compounds including cisplatin also exhibit marked inhibitory potential. Cisplatin is one of the most effective and broadly used anticancer drugs, especially for ovarian, testicular, bladder, lung and esophageal carcinomas. It induces apoptosis generally considered to be mediated by the formation of covalent DNA adducts, which block replication and transcription. A number of authors, including ourselves, have shown that DNA replication is arrested at platinum-adducts on template DNA, and this has been proposed as the responsible factor for the cytotoxicity of cisplatin. 9 -12 The most abundant DNA adducts formed by cisplatin are 1,2-intrastrand d(GpG) and d(ApG) cross-links, 65% and 25%, 13,14 respectively, so G-rich telomere DNA could be a preferred target. 15 From a preincubation experiment, we also noted that cisplatin-adduct formation on primer DNA suppressed the activity of partially purified rat telomerase. However, the results also indicated that cisplatin may directly interact with the enzyme molecule, a conclusion further supported by the finding of a platinum compound, compound E, that inhibited the telomerase acti...

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