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.

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Angiogenesis is crucial for tumor growth and hematogenous metastasis. Specifically expressed and functional protein molecules in angiogenic endothelial cells, especially on the plasma membrane, may be molecular targets for antiangiogenic drugs and drug delivery systems (DDS) in cancer therapy. To discover such target molecules, we performed subcellular proteome analysis of human umbilical vein endothelial cells (HUVECs) treated with or without vascular endothelial growth factor (VEGF) using 2‐dimensional difference in‐gel electrophoresis (2D‐DIGE) and matrix‐assisted laser desorption/ionization tandem time‐of‐flight mass spectrometry (MALDI‐TOF/TOF‐MS). Among the identified proteins, BiP/GRP78, a molecular chaperone, was highly expressed in the membrane/organelle fraction of HUVECs after VEGF treatment. The involvement of BiP in VEGF‐induced angiogenesis was examined by RNA interference. BiP knockdown significantly suppressed VEGF‐induced endothelial cell proliferation and VEGF‐induced phosphorylation of extracellular‐regulated kinase 1/2, phospholipase C‐γ, and VEGF receptor‐2 in HUVECs. Cell surface biotinylation analysis revealed that the cell surface expression of BiP was elevated in VEGF‐activated HUVECs. Aiming to apply BiP to a target molecule in liposomal DDS, we developed liposomes modified with the WIFPWIQL peptide, which has been shown to bind to BiP, and investigated its potential for cancer therapy. The WIFPWIQL‐modified liposomes (WIFPWIQL liposomes) were significantly taken up by VEGF‐activated HUVECs as compared to peptide‐unmodified liposomes. WIFPWIQL liposomes appeared to accumulate in tumor endothelial cells in vivo. WIFPWIQL liposomes containing doxorubicin significantly suppressed tumor growth and prolonged the survival of colon26 NL‐17 carcinoma cell‐bearing mice. In summary, BiP may regulate VEGF‐induced endothelial cell proliferation through VEGFR‐2‐mediated signaling and be an effective target molecule for cancer antineovascular therapy.

Phase relations in the system MgSiO3‐Al2O3 were investigated at pressures of 27–45 GPa and temperatures of 1700, 2000, and 2300 K using sintered diamond and tungsten carbide anvils in a multianvil apparatus. The bulk compositions in the MgSiO3‐Al2O3 binary system crystallize a phase assemblage of pyrope and corundum at pressures below 27 GPa and an assemblage of bridgmanite and corundum at pressures above 27 GPa regardless of temperatures. The solubility of Al2O3 in bridgmanite and that of MgSiO3 in corundum increases significantly with increasing temperature. The solubility of Al2O3 in bridgmanite increases from 6.7 mol % at 1700 K to 21.8 mol % at 2500 K under a constant pressure of 27 GPa. Bridgmanite becomes more aluminous with increasing pressure from 27 to 45 GPa at a given temperature. The MgSiO3 content in corundum increases with increasing pressure at pressure lower than 27 GPa, while it decreases at pressure higher than 27 GPa. Our results suggest that bridgmanite can incorporate a considerably higher Al2O3 content than that of the pyrope composition (25 mol % Al2O3). The present study further suggests that the entire Al2O3 component is accommodated into bridgmanite in the pyrolite lower mantle. However, Al2O3 cannot be fully accommodated into bridgmanite in the coldest parts of subducted slabs in the shallow part of the lower mantle, and therefore, additional phases such as MgAl2O4 with calcium ferrite‐type structure are necessary to host the excess Al2O3.

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Solids in nature can be generally classified into crystalline and non-crystalline states [1][2][3][4][5][6][7] , depending on whether long-range lattice periodicity is present in the material. The differentiation of the two states, however, could face fundamental challenges if the degree of long-range order in crystals is significantly reduced. Here we report a unique paracrystalline state of diamond that is distinct from either crystalline or amorphous diamond [8][9][10] . The paracrystalline diamond reported in this work, consisting of sub-nanometersized paracrystals that possess a well-defined crystalline medium-range order up to a few atomic shells 4,5,[11][12][13][14] , was synthesized in high-pressure high-temperature conditions (e.g., 30 GPa, 1600 K) employing fcc-C 60 as a precursor. The structural characteristics of paracrystalline diamond was identified through a combination of X-ray diffraction, highresolution transmission microscopy, and advanced molecular dynamics simulation. The formation of paracrystalline diamond is a result of densely distributed nucleation sites developed in compressed C 60 as well as pronounced second-nearest-neighbor short-range order in amorphous diamond due to strong sp 3 bonding. The discovery of paracrystalline diamond adds a new diamond form to the enriched carbon family 15-17 , which exhibits distinguishing physical properties and can be furthered exploited to develop new materials. Furthermore, this work reveals the missing link in the length-scale between amorphous and crystalline states across the structural landscape, which has profound implications for recognizing complex structures arising from amorphous materials.Amorphous solids refer to materials that do not possess long-range periodicity as exhibited in crystals [1][2][3][4][5][6][7][8][9][10][11] . Consequently, Bragg peaks associated with crystalline arrangements of atoms are absent or obscured in the diffraction signals of amorphous materials, which renders the recognition of their structural organizations notoriously difficult. Due to decades of research effort, it is now understood that structural ordering on the atomic level of amorphous solids is ubiquitous, as manifested by the short-to-medium-range ordering in metallic glasses [5][6][7] and the continuousrandom networks (CRN) of amorphous semiconductors 1-3 . Moving from the short range into the extended length-scale abutting the long-range scale, however, our understanding of the structural arrangements remains much more limited, and it is often complicated by capricious crystalline structural ordering encountered in amorphous materials 14,[18][19][20] . In an attempt to resolve this structural enigma, a paracrystalline structure model was proposed 11,20 , in which nanosized paracrystals, defined as severely distorted crystals, were introduced to the amorphous matrix to account for the crystalline medium range order (MRO). A crucial question to answer is, in the configurational space, are we able to identify a state of matter that is fully packed with...