dBRD9-A   Click here for help

GtoPdb Ligand ID: 10546

Compound class: Synthetic organic
Comment: This is an analogue of dBRD9, that was designed to achieve enhanced BRD9 degradation properties [1]. Like dBRD9 it is a PROTAC (proteolysis targeting chimera). dBRD9-A is a hybrid molecule that simultaneously engages the BRD9 bromodomain and recruits E3 ligase CRL4CRBN (using a pomalidomide-based module) to target BRD9 for destruction via E3 ligase-mediated ubiquitination and proteasomal degradation.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 11
Hydrogen bond donors 3
Rotatable bonds 19
Topological polar surface area 181.27
Molecular weight 779.36
XLogP 4.49
No. Lipinski's rules broken 2
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Canonical SMILES COc1cc(cc(c1CN(CC(=O)NCCCCCCCCNc1cccc2c1C(=O)N(C2=O)C1CCC(=O)NC1=O)C)OC)c1cn(C)c(=O)c2c1ccnc2
Isomeric SMILES COc1cc(cc(c1CN(CC(=O)NCCCCCCCCNc1cccc2c1C(=O)N(C2=O)C1CCC(=O)NC1=O)C)OC)c1cn(C)c(=O)c2c1ccnc2
InChI InChI=1S/C42H49N7O8/c1-47(23-31-34(56-3)20-26(21-35(31)57-4)30-24-48(2)40(53)29-22-43-19-16-27(29)30)25-37(51)45-18-10-8-6-5-7-9-17-44-32-13-11-12-28-38(32)42(55)49(41(28)54)33-14-15-36(50)46-39(33)52/h11-13,16,19-22,24,33,44H,5-10,14-15,17-18,23,25H2,1-4H3,(H,45,51)(H,46,50,52)
Bioactivity Comments
BRD9 is critical for cell growth of synovial sarcoma cells that are driven by the SS18-SSX fusion protein that is found in BAF (SWI/SNF) transcription complexes in these tumours. dBRD9-A-mediated BRD9 degradation has exhibited efficacy against these intractable tumour cells in vitro [1]. dBRD9-A promotes almost complete BRD9 degradation at low nanomolar concentrations (>90% degradation by 6 hours at 100 nM compound concentration in HSSY1 and SYO1 cells).
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
bromodomain containing 9 Hs None Binding 7.1 pIC50 - 1
pIC50 7.1 (IC50 8.31x10-8 M) [1]
Description: In vitro binding affinity determined by an AlphaScreen displacement ligand binding assay.