Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors.
Yang, Yaxi; Zhang, Rukang; Li, Zhaojun; Mei, Lianghe; Wan, Shili; Ding, Hong; Chen, Zhifeng; Xing, Jing; Feng, Huijin; Han, Jie; Jiang, Hualiang; Zheng, Mingyue; Luo, Cheng; Zhou, Bing; Journal of medicinal chemistry  (2020) –; doi:10.1021/acs.jmedchem.9b01721

data_1557183
_publ_section_title
;
 Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP
 Histone Acetyltransferases Inhibitors.
;
_journal_name_full               'Journal of medicinal chemistry'
_journal_paper_doi               10.1021/acs.jmedchem.9b01721
_journal_year                    2020
_chemical_absolute_configuration rmad
_chemical_formula_moiety         'C26 H28 N4 O5'
_chemical_formula_sum            'C26 H28 N4 O5'
_chemical_formula_weight         476.52
_space_group_crystal_system      tetragonal
_space_group_IT_number           76
_space_group_name_Hall           'P 4w'
_space_group_name_H-M_alt        'P 41'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2019-06-24
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   11.7728(11)
_cell_length_b                   11.7728(11)
_cell_length_c                   17.1159(15)
_cell_measurement_reflns_used    9919
_cell_measurement_temperature    173
_cell_measurement_theta_max      70.72
_cell_measurement_theta_min      3.752
_cell_volume                     2372.2(4)
_computing_cell_refinement       'SAINT v8.34A (Bruker, 2013)'
_computing_data_reduction        'SAINT v8.34A (Bruker, 2013)'
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL (Sheldrick, 2015)'
_computing_structure_solution    'ShelXT (Sheldrick, 2015)'
_diffrn_ambient_temperature      173
_diffrn_measured_fraction_theta_full 0.995
_diffrn_measured_fraction_theta_max 0.974
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0319
_diffrn_reflns_av_unetI/netI     0.0189
_diffrn_reflns_Laue_measured_fraction_full 0.995
_diffrn_reflns_Laue_measured_fraction_max 0.974
_diffrn_reflns_limit_h_max       14
_diffrn_reflns_limit_h_min       -14
_diffrn_reflns_limit_k_max       14
_diffrn_reflns_limit_k_min       -13
_diffrn_reflns_limit_l_max       19
_diffrn_reflns_limit_l_min       -19
_diffrn_reflns_number            26996
_diffrn_reflns_point_group_measured_fraction_full 0.980
_diffrn_reflns_point_group_measured_fraction_max 0.949
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         70.630
_diffrn_reflns_theta_min         3.754
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.770
_exptl_absorpt_correction_T_max  0.7534
_exptl_absorpt_correction_T_min  0.6980
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2014/5 (Bruker,2014/5) was used for absorption correction. wR2(int) was 0.0974 before and 0.0406 after correction. The Ratio of minimum to maximum transmission is 0.9265. The \l/2 correction factor is 0.00150.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.334
_exptl_crystal_description       block
_exptl_crystal_F_000             1008
_exptl_crystal_size_max          0.18
_exptl_crystal_size_mid          0.15
_exptl_crystal_size_min          0.12
_refine_diff_density_max         0.105
_refine_diff_density_min         -0.127
_refine_diff_density_rms         0.028
_refine_ls_abs_structure_details
;
 Flack x determined using 1916 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.01(6)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.018
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     318
_refine_ls_number_reflns         4335
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.018
_refine_ls_R_factor_all          0.0275
_refine_ls_R_factor_gt           0.0266
_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^)+(0.0432P)^2^+0.1886P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0691
_refine_ls_wR_factor_ref         0.0699
_reflns_Friedel_coverage         0.882
_reflns_Friedel_fraction_full    0.965
_reflns_Friedel_fraction_max     0.923
_reflns_number_gt                4207
_reflns_number_total             4335
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm9b01721_si_003.cif
_cod_data_source_block           cu_20180188-b015-1_0m
_cod_original_cell_volume        2372.2(5)
_cod_database_code               1557183
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.913
_shelx_estimated_absorpt_t_min   0.874
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2.a Ternary CH refined with riding coordinates:
 C8(H8)
2.b Secondary CH2 refined with riding coordinates:
 C6(H6A,H6B), C13(H13A,H13B), C9(H9A,H9B), C7(H7A,H7B), C18(H18A,H18B),
 C17(H17A,H17B)
2.c Aromatic/amide H refined with riding coordinates:
 N3(H3), N4(H4), C20(H20), C23(H23), C1(H1), C2(H2), C22(H22), C4(H4A), C3(H3A)
2.d Idealised Me refined as rotating group:
 C11(H11A,H11B,H11C), C26(H26A,H26B,H26C)
;
_olex2_submission_special_instructions 'No special instructions were received'