Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode.

General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under amino acid depletion. We initiated studies aiming at the discovery of novel GCN2 inhibitors as first-in-class antitumor agents and conducted modification of the substructure of sulfonamide derivatives with expected type I half binding on GCN2. Our synthetic strategy mainly corresponding to the αC-helix allosteric pocket of GCN2 led to significant enhancement in potency and a good pharmacokinetic profile in mice. In addition, compound 6d, which showed slow dissociation in binding on GCN2, demonstrated antiproliferative activity in combination with the asparagine-depleting agent asparaginase in an acute lymphoblastic leukemia (ALL) cell line, and it also displayed suppression of GCN2 pathway activation with asparaginase treatment in the ALL cell line and mouse xenograft model.

Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.

Antitumor activity of a novel and orally available inhibitor of serine palmitoyltransferase.

Metabolic reprogramming is an essential hallmark of neoplasia. Therefore, targeting cancer metabolism, including lipid synthesis, has attracted much interest in recent years. Serine palmitoyltransferase (SPT) plays a key role in the initial and rate-limiting step of de novo sphingolipid biosynthesis, and inhibiting SPT activity prevents the proliferation of certain cancer cells. Here, we identified a novel and orally available SPT inhibitor, compound-2. Compound-2 showed an anti-proliferative effect in several cancer cell models, reducing the levels of the sphingolipids ceramide and sphingomyelin. In the presence of compound-2, exogenously added S1P partially compensated the intracellular sphingolipid levels through the salvage pathway by partially rescuing compound-2-induced cytotoxicity. This suggested that the mechanism underlying the anti-proliferative effect of compound-2 involved the reduction of sphingolipid levels. Indeed, compound-2 promoted multinuclear formation with reduced endogenous sphingomyelin levels specifically in a compound-2-sensitive cell line, indicating that the effect was induced by sphingolipid reduction. Furthermore, compound-2 showed potent antitumor activity without causing significant body weight loss in the PL-21 acute myeloid leukemia mouse xenograft model. Therefore, SPT may be an attractive therapeutic anti-cancer drug target for which compound-2 may be a promising new drug.

[A case of endocrine cell carcinoma of the esophagus successfully treated by chemoradiotherapy].

The patient was a 74-year-old man who suffered from epigastric abdominal pain. He visited our hospital in April 2008. An esophageal endocrine cell carcinoma was pointed out by gastrointestinal endoscopy, and he was diagnosed as esophageal endoscopic cell carcinoma with mediastinum lymph node by CT scan(Stage IVa: cT3N4M0). Concurrent chemoradiotherapy using CDDP+EP was started. After two courses, the primary tumor was markedly reduced, and endoscopy showed only a scar. We diagnosed the patient as being in complete remission. However, CT showed a liver metastasis relapse in June 2009, and we started AMR as second-line chemotherapy. His general condition went into a decline, however, He died on October 2, 2009.

Capsule-endoscopic findings of ulcerative colitis patients.

BACKGROUND/AIMS: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by diffuse mucosal inflammation, traditionally regarded as being limited to the colorectum. Although several gastroduodenal lesions have also been reported recently in cases of UC, in general, small-bowel lesions in UC are believed to be extremely rare. The aim of this study was to examine the small bowel by capsule endoscopy in patients with UC. METHODS: The study was conducted in 23 well-documented UC patients and 23 control volunteers. The frequency of small-bowel lesions, the number of small-bowel lesions per patient and the capsule endoscopy score were comparatively evaluated between the two groups. RESULTS: Of the 23 UC patients, 13 (57%) showed small-bowel lesions, and 8 (35%) had erosions. There were significant differences in the frequency of the small-bowel lesions (p < 0.001) and erosions (p = 0.009) between the two groups. The capsule endoscopy score was correlated with the UC disease activity index (r = 0.718, p < 0.001). CONCLUSIONS: This is the first capsule-endoscopic study conducted to examine the small-bowel involvement in UC patients as compared with the healthy volunteers. It was concluded that UC, a chronic inflammatory bowel disease, can also involve the small bowel.