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_1557185
_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         'C25 H23 F4 N5 O5'
_chemical_formula_sum            'C25 H23 F4 N5 O5'
_chemical_formula_weight         549.48
_space_group_crystal_system      triclinic
_space_group_IT_number           1
_space_group_name_Hall           'P 1'
_space_group_name_H-M_alt        'P 1'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     iterative
_audit_creation_date             2019-08-08
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                96.5150(10)
_cell_angle_beta                 96.5150(10)
_cell_angle_gamma                107.35
_cell_formula_units_Z            4
_cell_length_a                   10.1492(4)
_cell_length_b                   10.1392(4)
_cell_length_c                   25.2626(11)
_cell_measurement_reflns_used    3751
_cell_measurement_temperature    173
_cell_measurement_theta_max      52.34
_cell_measurement_theta_min      4.27
_cell_volume                     2435.42(17)
_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    'olex2.solve (Bourhis et al., 2015)'
_diffrn_ambient_temperature      173.0
_diffrn_measured_fraction_theta_full 0.996
_diffrn_measured_fraction_theta_max 0.975
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0392
_diffrn_reflns_av_unetI/netI     0.0490
_diffrn_reflns_Laue_measured_fraction_full 0.996
_diffrn_reflns_Laue_measured_fraction_max 0.975
_diffrn_reflns_limit_h_max       12
_diffrn_reflns_limit_h_min       -12
_diffrn_reflns_limit_k_max       12
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       31
_diffrn_reflns_limit_l_min       -31
_diffrn_reflns_number            39047
_diffrn_reflns_point_group_measured_fraction_full 0.918
_diffrn_reflns_point_group_measured_fraction_max 0.876
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         74.640
_diffrn_reflns_theta_min         1.782
_exptl_absorpt_coefficient_mu    1.091
_exptl_absorpt_correction_T_max  0.6572
_exptl_absorpt_correction_T_min  0.4512
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details   Bruker;sadabs;2016
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.499
_exptl_crystal_description       needle
_exptl_crystal_F_000             1136
_exptl_crystal_size_max          0.08
_exptl_crystal_size_mid          0.05
_exptl_crystal_size_min          0.04
_refine_diff_density_max         0.182
_refine_diff_density_min         -0.252
_refine_diff_density_rms         0.035
_refine_ls_abs_structure_details
;
 Flack x determined using 7084 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.00(5)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.043
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     1410
_refine_ls_number_reflns         17525
_refine_ls_number_restraints     1311
_refine_ls_restrained_S_all      1.006
_refine_ls_R_factor_all          0.0361
_refine_ls_R_factor_gt           0.0342
_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^)+(0.0354P)^2^+0.4591P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0853
_refine_ls_wR_factor_ref         0.0873
_reflns_Friedel_coverage         0.796
_reflns_Friedel_fraction_full    0.840
_reflns_Friedel_fraction_max     0.776
_reflns_number_gt                16929
_reflns_number_total             17525
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm9b01721_si_004.cif
_cod_data_source_block           p1_a
_cod_original_cell_volume        2435.37(17)
_cod_database_code               1557185
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.958
_shelx_estimated_absorpt_t_min   0.918
_olex2_refinement_description
;
1. Twinned data refinement
 Scales: 0.5799(10)
 0.4201(10)
2. 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
3. Rigid body (RIGU) restrains
 All non-hydrogen atoms
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
4.a Ternary CH refined with riding coordinates:
 C9(H9), C039(H039), C03V(H03V), C042(H042)
4.b Secondary CH2 refined with riding coordinates:
 C7(H7A,H7B), C01L(H01B,H01C), C21(H21A,H21B), C02A(H02H,H02I), C12(H12A,H12B),
  C02I(H02A,H02B), C02L(H02D,H02E), C02N(H02F,H02G), C02X(H02J,H02K), C030(H03I,
 H03J), C037(H03K,H03L), C03A(H03R,H03S), C03P(H03W,H03X), C03T(H03D,H03F),
 C22(H22A,H22B), C03X(H03G,H03H), C043(H04A,H04B), C8(H8A,H8B), C048(H04C,H04D),
  C04C(H04F,H04G)
4.c Aromatic/amide H refined with riding coordinates:
 N00G(H00G), N4(H4), C00N(H00N), N00W(H00W), N3(H3), N5(H5), N015(H015),
 N019(H019), N01A(H01A), C01C(H01D), C01I(H01I), C01N(H01N), C01P(H01P),
 C17(H17), C01U(H01U), C01Y(H01Y), C20(H20), N029(H029), N02C(H02C), C02R(H02R),
  C18(H18), C031(H031), C034(H034), C03E(H03E), C03G(H03T), N03H(H03M),
 C03K(H03U), C03N(H03N), N20(H20A), C03Y(H03Y), C040(H040), C6(H6), C044(H044),
 C2(H2), C3(H3A), C04B(H04E)
4.d Idealised Me refined as rotating group:
 C24(H24A,H24B,H24C), C03B(H03A,H03B,H03C), C03R(H03O,H03P,H03Q), C50(H50A,
 H50B,H50C)
;
_olex2_submission_special_instructions 'No special instructions were received'