Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as a promising target for the treatment of several diseases, including neurological disorders and cancer. We report here the crystal structures of two IDO1/IDO1 inhibitor complexes, one of which shows that Amg-1 is directly bound to the heme iron of IDO1 with a clear induced fit. We also describe the identification and preliminary optimization of imidazothiazole derivatives as novel IDO1 inhibitors. Using our crystal structure information and structure−activity relationships (SAR) at the pocket-B of IDO1, we found a series of urea derivatives as potent IDO1 inhibitors and revealed that generation of an induced fit and the resulting interaction with Phe226 and Arg231 are essential for potent IDO1 inhibitory activity. The results of this study are very valuable for understanding the mechanism of IDO1 activation, which is very important for structure-based drug design (SBDD) to discover potent IDO1 inhibitors.

Anaphase‐promoting complex (APC) is activated by two regulatory proteins, Cdc20 and Cdh1. In yeast and Drosophila, Cdh1‐dependent APC (Cdh1–APC) activity targets mitotic cyclins from the end of mitosis to the G1 phase. To investigate the function of Cdh1 in vertebrate cells, we generated clones of chicken DT40 cells disrupted in their Cdh1 loci. Cdh1 was dispensable for viability and cell cycle progression. However, similarly to yeast and Drosophila, loss of Cdh1 induced unscheduled accumulation of mitotic cyclins in G1, resulting in abrogation of G1 arrest caused by treatment with rapamycin, an inducer of p27Kip1. Further more, we found that Cdh1−/− cells fail to maintain DNA damage‐induced G2 arrest and that Cdh1–APC is activated by X‐irradiation‐induced DNA damage. Thus, activation of Cdh1–APC plays a crucial role in both cdk inhibitor‐dependent G1 arrest and DNA damage‐induced G2 arrest.

V20, VS5, age, and PFS on baseline CT are independent and significant risk factors for occurrence of severe RP. Combining these factors may improve the predictability of severe RP.

To find HDAC8-selective inhibitors, we designed a library of HDAC inhibitor candidates, each containing a zinc-binding group that coordinates with the active-site zinc ion, linked via a triazole moiety to a capping structure that interacts with residues on the rim of the active site. These compounds were synthesized by using click chemistry. Screening identified HDAC8-selective inhibitors including C149 (IC(50) = 0.070 μM), which was more potent than PCI-34058 (6) (IC(50) = 0.31 μM), a known HDAC8 inhibitor. Molecular modeling suggested that the phenylthiomethyl group of C149 binds to a unique hydrophobic pocket of HDAC8, and the orientation of the phenylthiomethyl and hydroxamate moieties (fixed by the triazole moiety) is important for the potency and selectivity. The inhibitors caused selective acetylation of cohesin in cells and exerted growth-inhibitory effects on T-cell lymphoma and neuroblastoma cells (GI(50) = 3-80 μM). These findings suggest that HDAC8-selective inhibitors have potential as anticancer agents.

The purpose of this study is to determine the incidence, clinical characteristics and risk factors of postradiation pelvic insufficiency fracture (PIF) in women with uterine cervical cancer. We reviewed the medical records of 126 patients who received definitive radiotherapy (RT) for uterine cervical cancer between 2003 and 2009 at our institution. Among them, 99 patients who underwent at least one computed tomography (CT) or magnetic resonance imaging of the pelvis during their follow-up at more than 6 months were included in this analysis. The relationship between the incidence of PIF and several patient- and treatment-related factors was analyzed. The median follow-up period was 21 months. Of the 126 patients, 33 (with a total of 50 lesions) were diagnosed with PIF. The 2-year cumulative incidence was 32%. Univariate analysis showed that age ≥70 years (P= 0.0010), postmenopausal state (P = 0.0013), and lower CT density of bone and bone marrow (P= 0.020) significantly related to PIF. In a multivariate analysis, of the 59 patients whose CT densities were evaluable, lower CT density was the only significant factor associated with PIF (P = 0.0026). In conclusion, postradiation PIFs were detected in a considerable number of patients after definitive RT for cervical cancer. Predisposing factors were older age, postmenopausal state, and decreased density of bone and bone marrow on CT.