Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T56510 Target Info
Target Name Apoptosis regulator Bcl-xL (BCL-xL)
Synonyms Bcl2like protein 1; Bcl2L1; Bcl2-L-1; Bcl-XL; Bcl-2-like protein 1; BCLX; BCL2L; Apoptosis regulator Bcl-X
Target Type Clinical trial Target
Gene Name BCL2L1
Biochemical Class B-cell lymphoma Bcl-2
UniProt ID
B2CL1_HUMAN
Ligand General Information  Top
Ligand Name N-(4-hydroxyphenyl)-3-[6-[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide Ligand Info
Canonical SMILES C1CCN2C(=C(C=C2C3=CC4=C(C=C3C(=O)N5CC6=CC=CC=C6CC5CN7CCOCC7)OCO4)C(=O)N(C8=CC=CC=C8)C9=CC=C(C=C9)O)C1
InChI 1S/C43H42N4O6/c48-34-15-13-32(14-16-34)47(31-10-2-1-3-11-31)43(50)37-23-39(45-17-7-6-12-38(37)45)35-24-40-41(53-28-52-40)25-36(35)42(49)46-26-30-9-5-4-8-29(30)22-33(46)27-44-18-20-51-21-19-44/h1-5,8-11,13-16,23-25,33,48H,6-7,12,17-22,26-28H2/t33-/m0/s1
InChIKey VYXJULKGMXJVGI-XIFFEERXSA-N
PubChem Compound ID 71654876
Drug Binding Sites of Target  Top
PDB ID: 6GL8      Crystal structure of Bcl-2 in complex with the novel orally active inhibitor S55746
Method X-ray diffraction Resolution 1.40 Å Mutation Yes [1]
PDB Sequence
GSYDNREIVM
16
KYIHYKLSQR
26
GYEWDAGADE
48
SEVVHKTLRE
99
AGDDFSRRYR
109

RDFAEMSSQL
119
HLTPFTARGR
129
FATVVEELFR
139
DGVNWGRIVA
149
FFEFGGVMCV
159

ESVNREMSPL
169
VDNIALWMTE
179
YLNRHLHTWI
189
QDNGGWDAFV
199
ELYG
Residue
Distance (Å)
PHE104
3.452
TYR108
3.568
ASP111
3.433
PHE112
3.619
MET115
3.705
GLN118
3.331
LEU119
4.021
VAL133
3.708
Residue
Distance (Å)
GLU136
3.791
LEU137
3.678
GLY145
3.306
ARG146
3.367
ALA149
2.682
PHE150
4.800
GLU152
3.842
PHE153
3.350
PDB ID: 6O0O      crystal structure of BCL-2 G101V mutation with S55746
Method X-ray diffraction Resolution 2.00 Å Mutation Yes [2]
PDB Sequence
YDNREIVMKY
18
IHYKLSQRGY
28
EWDAEVVHLT
55
LRQAVDDFSR
65
RYRRDFAEMS
75

SQLHLTPFTA
85
RGRFATVVEE
95
LFRDGVNWGR
105
IVAFFEFGGV
115
MCVESVNREM
125

SPLVDNIALW
135
MTEYLNRHLH
145
TWIQDNGGWD
155
AFVELYG
Residue
Distance (Å)
PHE63
3.621
TYR67
3.459
ASP70
3.152
PHE71
3.622
MET74
3.490
ARG88
3.610
VAL92
3.608
GLU95
3.174
Residue
Distance (Å)
LEU96
3.503
GLY104
3.221
ARG105
3.362
ALA108
2.837
PHE109
4.942
GLU111
3.804
PHE112
3.344
References  Top
REF 1 S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth. Oncotarget. 2018 Apr 13;9(28):20075-20088.
REF 2 Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat Commun. 2019 Jun 3;10(1):2385.

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