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Supporting material Discovery of a Series of Dihydroquinoxalin-2(1H)- ones as Selective BET Inhibitors from a Dual PLK1-BRD4 inhibitor Jianping Hu a,c,# , Yingqing Wang b,# , Yanlian Li a,# , Lin Xu b,c , Danyan Cao a , ShanShan Song b , Mohammadali Soleimani Damaneh b,c , Xin Wang a , Tao Meng a , Yue-Lei Chen a , Jingkang Shen a,* , Zehong Miao b,* , Bing Xiong a,* a Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China b Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China c University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China # These authors contributed equally * Corresponding authors. Tel: +86 21 50806600 ext. 5412 fax: +86 21 50807088. Email: (B. X.) [email protected] ; (Z. M.) [email protected] ; (J. S.) [email protected]
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Supporting material
Discovery of a Series of Dihydroquinoxalin-2(1H)-ones as Selective
BET Inhibitors from a Dual PLK1-BRD4 inhibitor
Jianping Hua,c,#, Yingqing Wangb,#, Yanlian Lia,# , Lin Xub,c, Danyan Caoa, ShanShan Songb,
Mohammadali Soleimani Damaneh b,c, Xin Wanga, Tao Menga, Yue-Lei Chena, Jingkang Shena,*,
Zehong Miaob,*, Bing Xionga,*
aDepartment of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute
of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203,
China
bDivision of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai
201203, China
cUniversity of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China
#These authors contributed equally
*Corresponding authors. Tel: +86 21 50806600 ext. 5412 fax: +86 21 50807088. Email: (B. X.)
[email protected]; (Z. M.) [email protected]; (J. S.) [email protected]
Contents:
Table S1. The method of chiral column separation of compounds 48 and 51.
Figure S1. The spectra of chiral column separation of compound 48.
Figure S2. The spectra of chiral column separation of compound 51.
Table S2. Data collection and refinement statistics of four crystal structures
Figure S3. Omit maps of compound 52Figure S4. Superimpose the minimized 53 with the conformation extracted from the
co-crystal structure
Table S3. Bromodomain selectivity test results of compound 54.
Figure S5. The graphs of cell viability for representative compounds 36, 48, 51, 52,
54, I-BET762 and (+)-JQ-1.
Figure S6. 1H and 13C NMR spectra of some potent BRD4 inhibitors.
Table S1. The method of chiral column separation of compounds 48 and 51.
Column Superchiral S-ADColumn size 0.46 cm I.D. × 15 cm LInjection 5 ulMobile phase CO2/IPA=70/30Flow rate 3.0 ml/minWave length UV 254 nmTemperature 35 ℃
Peak No. RT(min) Area% T.Plate1 2.299 100.000 7461
Peak No. RT(min) Area% T.Plate1 2.319 0.258 62302 2.482 99.742 7845
Figure S1. The spectra of chiral column separation of compound 48.
Peak No. RT(min) Area% T.Plate1 2.997 99.395 68302 3.481 0.605 6416
Peak No. RT(min) Area% T.Plate1 3.088 0.629 65222 3.349 99.371 7314
Figure S2. The spectra of chiral column separation of compound 51.
Table S2. Data collection and refinement statistics of four crystal structures.
PDB Entry 5XHY 5XI3 5XI2 5XI4
Ligand ID 19 35 52 53
Resolution range31.06 - 1.79 30.33 - 1.674 40.59 - 1.909 32.01 - 1.486
Space groupP 21 21 21 P 21 21 21 P 21 21 21 P 21 21 21
Unit cell33.846 47.718
78.18
90 90 90
32.478 47.581
78.714
90 90 90
34.713 47.555
77.923
90 90 90
35.124 47.421
77.817
90 90 90
Total reflections175198 28356 20585 41603
Unique reflections12498 14195 10298 20854
Multiplicity14.0 2.0 2.0 2.0
Completeness (%)99.88 96.83 97.95 94.40
Mean I/sigma(I)12.21 17.43 13.73 15.97
Wilson B-factor24.24 15.00 22.22 13.74
R-merge0.1963 0.03421 0.03738 0.02825
R-meas0.2042 0.04838 0.05286 0.03995
R-pim0.05553 0.03421 0.03738 0.02825
CC1/20.995 0.999 0.999 0.999
CC*0.999 1 1 1
Reflections used in refinement
12485 14195 10294 20839
Reflections used for R-free
633 683 (65) 503 1010
R-work0.2120 0.1867 0.1973 0.2171
R-free0.2641 0.2179 0.2374 0.2533
CC(work)0.958 0.960 0.962 0.952
CC(free)0.923 0.961 0.969 0.946
Number of non-hydrogen atoms
1120 1197 1143 1176
macromolecules1041 1041 1041 1041
ligands1 1 1 1
solvent52 131 76 109
Protein residues124 124 124 124
RMS(bonds)0.006 0.006 0.007 0.008
RMS(angles)0.79 0.83 0.83 0.84
Ramachandran favored (%)
100.00 98.36 99.18 99.18
Ramachandran allowed (%)
0.00 1.64 0.82 0.82
Clashscore2.37 5.21 3.78 6.15
Average B-factor25.21 18.83 26.08 20.56
macromolecules24.87 17.53 25.76 19.93
ligands23.88 27.08 21.79 16.08
solvent32.69 27.62 31.87 27.70
A. B.
C.
Figure S3. Omit maps of compound 52. A and B are 2Fo-Fc map, and C is Fo-Fc map.
Figure S4. Superimpose the minimized 53 (shown in green color) with the
conformation extracted from the co-crystal structure (shown in yellow color).
Table S3. Bromodomain selectivity test results of compound 54.
Target 54
Gene Symbol % Ctrl@1 μM
ATAD2A 100
ATAD2B 100
BAZ2A 83
BAZ2B 82
BRD1 57
BRD2(1) 0.9
BRD2(2) 0
BRD3(1) 0.1
BRD3(2) 0.3
BRD4(1) 1.7
BRD4(2) 0.05
BRD7 97
BRD9 77
BRDT(1) 3.1
BRDT(2) 0
BRPF1 100
BRPF3 100
CECR2 83
CREBBP 67
EP300 47
FALZ 96
GCN5L2 63
PBRM1(2) 100
PBRM1(5) 94
PCAF 96
SMARCA2 73
SMARCA4 95
TAF1(2) 85
TAF1L(2) 88
TRIM24(PHD,Bromo.) 80
TRIM33(PHD,Bromo.) 99
BRWD1 73
Figure S5. The graphs of cell viability for representative compounds 36, 48, 51,
52, 54, I-BET762 and (+)-JQ-1. The percentage of cell viability was calculated as:
cell viability (%) =A450treated/A450control×100%. The averaged IC50 values were
determined with the Logit method from two independent tests using SoftMax Pro5
software.
Figure S6. 1H and 13C NMR spectra of some potent BRD4 inhibitors.
