An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androge... more We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.
Aberrant signaling of ErbB family members, HER2 and EGFR, is implicated in many human cancers and... more Aberrant signaling of ErbB family members, HER2 and EGFR, is implicated in many human cancers and HER2 expression is predictive of human disease recurrence and prognosis. Small molecule kinase inhibitors of EGFR and of both HER2 and EGFR have received approval for the treatment of cancer. We present the first high resolution crystal structure of the kinase domain of HER2 in complex with a selective inhibitor to understand protein activation, inhibition and function at the molecular level. HER2 kinase domain crystallizes as a dimer and suggests evidence for an allosteric mechanism of activation comparable to previously reported activation mechanisms for EGFR and HER4. A unique Gly-rich region in HER2 following the α-helixC is responsible for increased conformational flexibility within the active-site and could explain the low intrinsic catalytic activity previously reported for HER2. In addition, we solved the crystal structure of the kinase domain of EGFR in complex with a HER2/EGFR...
Figure 1. Stereo views of σA-weighted 2|Fo|-|Fc| composite omit electron density maps contoured a... more Figure 1. Stereo views of σA-weighted 2|Fo|-|Fc| composite omit electron density maps contoured at 1σ and rendered within 1 A of the heme and substrate for the P450 2A6 (a) coumarin or (b) methoxsalen complexes. Coumarin and methoxsalen are stabilized by hydrogen bonding with Asn297, which places the carbon atom to be oxidized 3.2 ± 0.13 A (coumarin) or 3.8 ± 0.09 A (methoxsalen) from the heme iron. The distances are shown as a red dotted line and the values quoted for distances are the mean and standard deviation for the four molecules in the asymmetric unit. The peptide backbone is represented as a thin gray coil, and side chains are rendered as stick figures with the following colors for atoms: carbons are colored gray for the protein or yellow for substrates, oxygens are red, and nitrogens are blue. The heme group is colored salmon. These molecular graphics images were generated using PyMOL (pymol.sourceforge.net). The Crystal Structure of Human, Nicotine Metabolizing Cytochrome...
Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-... more Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated ...
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androge... more We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.
Aberrant signaling of ErbB family members, HER2 and EGFR, is implicated in many human cancers and... more Aberrant signaling of ErbB family members, HER2 and EGFR, is implicated in many human cancers and HER2 expression is predictive of human disease recurrence and prognosis. Small molecule kinase inhibitors of EGFR and of both HER2 and EGFR have received approval for the treatment of cancer. We present the first high resolution crystal structure of the kinase domain of HER2 in complex with a selective inhibitor to understand protein activation, inhibition and function at the molecular level. HER2 kinase domain crystallizes as a dimer and suggests evidence for an allosteric mechanism of activation comparable to previously reported activation mechanisms for EGFR and HER4. A unique Gly-rich region in HER2 following the α-helixC is responsible for increased conformational flexibility within the active-site and could explain the low intrinsic catalytic activity previously reported for HER2. In addition, we solved the crystal structure of the kinase domain of EGFR in complex with a HER2/EGFR...
Figure 1. Stereo views of σA-weighted 2|Fo|-|Fc| composite omit electron density maps contoured a... more Figure 1. Stereo views of σA-weighted 2|Fo|-|Fc| composite omit electron density maps contoured at 1σ and rendered within 1 A of the heme and substrate for the P450 2A6 (a) coumarin or (b) methoxsalen complexes. Coumarin and methoxsalen are stabilized by hydrogen bonding with Asn297, which places the carbon atom to be oxidized 3.2 ± 0.13 A (coumarin) or 3.8 ± 0.09 A (methoxsalen) from the heme iron. The distances are shown as a red dotted line and the values quoted for distances are the mean and standard deviation for the four molecules in the asymmetric unit. The peptide backbone is represented as a thin gray coil, and side chains are rendered as stick figures with the following colors for atoms: carbons are colored gray for the protein or yellow for substrates, oxygens are red, and nitrogens are blue. The heme group is colored salmon. These molecular graphics images were generated using PyMOL (pymol.sourceforge.net). The Crystal Structure of Human, Nicotine Metabolizing Cytochrome...
Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-... more Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated ...
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