Identification of ligand linkage vectors for the development of p300/CBP degraders
Brownsey, Duncan K.; Rowley, Ben C.; Gorobets, Evgueni; Mihara, Koichiro; Maity, Ranjan; Papatzimas, James W.; Gelfand, Benjamin S.; Hollenberg, Morley D.; Bahlis, Nizar J.; Derksen, Darren J.; RSC Medicinal Chemistry  (2022) –; doi:10.1039/D1MD00070E

data_7244895
_publ_section_title
;
 Identification of ligand linkage vectors for the development of p300/CBP
 degraders
;
_journal_name_full               'RSC Medicinal Chemistry'
_journal_paper_doi               10.1039/D1MD00070E
_journal_year                    2022
_chemical_absolute_configuration ad
_chemical_formula_moiety         '2(C11 H8 Br N O3)'
_chemical_formula_sum            'C22 H16 Br2 N2 O6'
_chemical_formula_weight         564.19
_space_group_crystal_system      orthorhombic
_space_group_IT_number           19
_space_group_name_Hall           'P 2ac 2ab'
_space_group_name_H-M_alt        'P 21 21 21'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2021-01-27
_audit_creation_method
;
Olex2 1.3
(compiled 2020.11.12 svn.r5f609507 for OlexSys, GUI svn.r6226)
;
_audit_update_record
;
2021-03-04 deposited with the CCDC.	2022-04-12 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   8.1112(2)
_cell_length_b                   8.1755(3)
_cell_length_c                   32.6852(9)
_cell_measurement_reflns_used    9964
_cell_measurement_temperature    173
_cell_measurement_theta_max      72.150
_cell_measurement_theta_min      2.704
_cell_volume                     2167.46(11)
_computing_cell_refinement       'SAINT V8.40A (Bruker, 2019)'
_computing_data_reduction        'SAINT V8.40A (Bruker, 2019)'
_computing_molecular_graphics    'Olex2 1.3 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.3 (Dolomanov et al., 2009)'
_computing_structure_refinement  'XL  (Sheldrick, 2008)'
_computing_structure_solution    'SHELXT 2018/2 (Sheldrick, 2018)'
_diffrn_ambient_temperature      173
_diffrn_detector                 'Bruker APEX2 area detector'
_diffrn_detector_area_resol_mean 7.9
_diffrn_detector_type            'CCD area detector'
_diffrn_measured_fraction_theta_full 0.997
_diffrn_measured_fraction_theta_max 0.997
_diffrn_measurement_device       'three-circle diffractometer'
_diffrn_measurement_device_type  'Bruker SMART APEX2 area detector'
_diffrn_measurement_method       '\w and \f scans'
_diffrn_radiation_monochromator  'mirror optics'
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0556
_diffrn_reflns_av_unetI/netI     0.0549
_diffrn_reflns_Laue_measured_fraction_full 0.997
_diffrn_reflns_Laue_measured_fraction_max 0.997
_diffrn_reflns_limit_h_max       9
_diffrn_reflns_limit_h_min       -9
_diffrn_reflns_limit_k_max       8
_diffrn_reflns_limit_k_min       -9
_diffrn_reflns_limit_l_max       37
_diffrn_reflns_limit_l_min       -39
_diffrn_reflns_number            14513
_diffrn_reflns_point_group_measured_fraction_full 0.998
_diffrn_reflns_point_group_measured_fraction_max 0.998
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         68.241
_diffrn_reflns_theta_min         2.704
_diffrn_source                   'microfocus sealed X-ray tube'
_diffrn_source_current           0.64
_diffrn_source_power             0.0285824
_diffrn_source_type              'Incoatec I\ms'
_diffrn_source_voltage           44.66
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    5.123
_exptl_absorpt_correction_T_max  0.7536
_exptl_absorpt_correction_T_min  0.5659
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
SADABS-2016/2 (Bruker,2016/2) was used for absorption correction.
wR2(int) was 0.1024 before and 0.0673 after correction.
The Ratio of minimum to maximum transmission is 0.7509.
The \l/2 correction factor is Not present.
;
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.729
_exptl_crystal_description       plate
_exptl_crystal_F_000             1120
_exptl_crystal_size_max          0.332
_exptl_crystal_size_mid          0.226
_exptl_crystal_size_min          0.038
_refine_diff_density_max         0.571
_refine_diff_density_min         -0.545
_refine_diff_density_rms         0.096
_refine_ls_abs_structure_details
;
 Flack x determined using 1430 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.069(16)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.170
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     327
_refine_ls_number_reflns         3939
_refine_ls_number_restraints     210
_refine_ls_restrained_S_all      1.140
_refine_ls_R_factor_all          0.0555
_refine_ls_R_factor_gt           0.0533
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0132P)^2^+7.0937P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1256
_refine_ls_wR_factor_ref         0.1267
_reflns_Friedel_coverage         0.719
_reflns_Friedel_fraction_full    0.999
_reflns_Friedel_fraction_max     0.998
_reflns_number_gt                3774
_reflns_number_total             3939
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d1md00070e2.cif
_cod_data_source_block           db-3-267_2nd
_cod_database_code               7244895
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.829
_shelx_estimated_absorpt_t_min   0.281
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups
2. Restrained distances
 C6-C4 \\sim C4A-C6 \\sim C18-C15 \\sim C18-C15A
 with sigma of 0.04
 C6-C5A \\sim C6-C5 \\sim C17-C16A \\sim C17-C16
 with sigma of 0.02
 C5-C4 \\sim C5A-C4A \\sim C16-C15 \\sim C16A-C15A
 with sigma of 0.02
 C4A-C3 \\sim C4-C3 \\sim C15-C14 \\sim C15A-C14
 with sigma of 0.02
 C14-C16A \\sim C14-C16 \\sim C3-C5 \\sim C3-C5A
 with sigma of 0.04
3. Uiso/Uaniso restraints and constraints
C14 \\sim C15 \\sim C15A \\sim C16 \\sim C16A \\sim C17: within 3A with sigma
of 0.01 and sigma for terminal atoms of 0.02 within 3A
C3 \\sim C4 \\sim C4A \\sim C5 \\sim C5A \\sim C6: within 3A with sigma of 0.01
and sigma for terminal atoms of 0.02 within 3A
4. Others
 Sof(C15A)=Sof(H15C)=Sof(H15D)=Sof(C16A)=Sof(H16C)=Sof(H16D)=1-FVAR(1)
 Sof(C15)=Sof(H15A)=Sof(H15B)=Sof(C16)=Sof(H16A)=Sof(H16B)=FVAR(1)
 Sof(C4A)=Sof(H4AA)=Sof(H4AB)=Sof(C5A)=Sof(H5AA)=Sof(H5AB)=1-FVAR(2)
 Sof(C4)=Sof(H4A)=Sof(H4B)=Sof(C5)=Sof(H5A)=Sof(H5B)=FVAR(2)
5.a Secondary CH2 refined with riding coordinates:
 C4(H4A,H4B), C4A(H4AA,H4AB), C5(H5A,H5B), C5A(H5AA,H5AB), C15(H15A,H15B),
 C15A(H15C,H15D), C16(H16A,H16B), C16A(H16C,H16D)
5.b Aromatic/amide H refined with riding coordinates:
 N1(H1), C8(H8), C9(H9), C11(H11), N2(H2), C19(H19), C20(H20), C22(H22)
;
_shelx_res_checksum              45937
_olex2_submission_special_instructions 'No special instructions were received'