3L17
Discovery of (thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer
X-RAY DIFFRACTION
Crystallization
| Crystalization Experiments | ||||
|---|---|---|---|---|
| ID | Method | pH | Temperature | Details |
| 1 | VAPOR DIFFUSION, HANGING DROP | 8.5 | 289 | PEG 3350, 0.2M NH4SO4, 0.1M Tris-HCl 8.5, vapor diffusion, hanging drop, temperature 289K |
| Crystal Properties | |
|---|---|
| Matthews coefficient | Solvent content |
| 2.35 | 47.76 |
Crystal Data
| Unit Cell | |
|---|---|
| Length ( Å ) | Angle ( ˚ ) |
| a = 144.095 | α = 90 |
| b = 67.727 | β = 96.07 |
| c = 107.455 | γ = 90 |
| Symmetry | |
|---|---|
| Space Group | C 1 2 1 |
Diffraction
| Diffraction Experiment | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ID # | Crystal ID | Scattering Type | Data Collection Temperature | Detector | Detector Type | Details | Collection Date | Monochromator | Protocol | |||||
| 1 | 1 | x-ray | CCD | ADSC QUANTUM 315 | 2006-06-09 | M | SINGLE WAVELENGTH | |||||||
| Radiation Source | |||||
|---|---|---|---|---|---|
| ID # | Source | Type | Wavelength List | Synchrotron Site | Beamline |
| 1 | SYNCHROTRON | ALS BEAMLINE 5.0.2 | 1.0 | ALS | 5.0.2 |
Data Collection
| Overall | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ID # | Resolution (High) | Resolution (Low) | Percent Possible (Observed) | R Merge I (Observed) | Net I Over Average Sigma (I) | Redundancy | Number Reflections (All) | Number Reflections (Observed) | Observed Criterion Sigma (F) | Observed Criterion Sigma (I) | B (Isotropic) From Wilson Plot | ||||||||
| 1 | 3 | 50 | 97.8 | 0.074 | 12.8 | 3.5 | 20541 | ||||||||||||
| Highest Resolution Shell | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ID # | Resolution (High) | Resolution (Low) | Percent Possible (All) | Percent Possible (Observed) | R Merge I (Observed) | Mean I Over Sigma (Observed) | Redundancy | Number Unique Reflections (All) | |||||||||||
| 1 | 3 | 3.11 | 83.1 | 0.362 | 2.7 | 1740 | |||||||||||||
Refinement
| Statistics | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Diffraction ID | Structure Solution Method | Cross Validation method | Starting model | Resolution (High) | Resolution (Low) | Number Reflections (Observed) | Number Reflections (R-Free) | Percent Reflections (Observed) | R-Factor (Observed) | R-Work | R-Free | R-Free Selection Details | Mean Isotropic B | ||||||
| X-RAY DIFFRACTION | MOLECULAR REPLACEMENT | THROUGHOUT | PDB ENTRY 1E8X | 3 | 45.18 | 20480 | 1042 | 97.96 | 0.218 | 0.216 | 0.271 | RANDOM | 101.362 | ||||||
| Temperature Factor Modeling | ||||||
|---|---|---|---|---|---|---|
| Anisotropic B[1][1] | Anisotropic B[1][2] | Anisotropic B[1][3] | Anisotropic B[2][2] | Anisotropic B[2][3] | Anisotropic B[3][3] | |
| -0.02 | 1.84 | 2.01 | -1.6 | |||
| RMS Deviations | |
|---|---|
| Key | Refinement Restraint Deviation |
| r_dihedral_angle_2_deg | 38.488 |
| r_dihedral_angle_3_deg | 18.689 |
| r_dihedral_angle_4_deg | 18.515 |
| r_dihedral_angle_1_deg | 6.63 |
| r_scangle_it | 1.357 |
| r_angle_refined_deg | 1.316 |
| r_angle_other_deg | 0.885 |
| r_scbond_it | 0.879 |
| r_mcangle_it | 0.65 |
| r_mcbond_it | 0.552 |
| Non-Hydrogen Atoms Used in Refinement | |
|---|---|
| Non-Hydrogen Atoms | Number |
| Protein Atoms | 6820 |
| Nucleic Acid Atoms | |
| Solvent Atoms | |
| Heterogen Atoms | 34 |
Software
| Software | |
|---|---|
| Software Name | Purpose |
| DENZO | data reduction |
| SCALEPACK | data scaling |
| PHASER | phasing |
| REFMAC | refinement |
| PDB_EXTRACT | data extraction |
