DD-03-171   Click here for help

GtoPdb Ligand ID: 10535

Compound class: Synthetic organic
Comment: DD-03-171 is a cereblon (CRBN)-engaging degrader (or PROTAC; proteolysis targeting chimera) of BTK protein [1]. The BTK inhibitor portion of DD-03-171 is derived from CGI1746, and this is conjugated to thalidomide using a saturated hydrocarbon linker to create the hybrid molecule. DD-03-171 produces potent antiproliferative effects on lymphoma cells in vitro and on patient-derived xenografts in vivo. It is suggested that DD-03-171's mechanism of action may be able to overcome tumour resistance to ibrutinib therapy.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 16
Hydrogen bond donors 5
Rotatable bonds 21
Topological polar surface area 224.25
Molecular weight 990.48
XLogP 7.17
No. Lipinski's rules broken 3
SMILES / InChI / InChIKey
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Canonical SMILES O=C(CNc1cccc2c1C(=O)N(C2=O)C1CCC(=O)NC1=O)NCCCCCCN1CCN(CC1)C(=O)c1ccc(cc1)Nc1nc(cn(c1=O)C)c1cccc(c1C)NC(=O)c1ccc(cc1)C(C)(C)C
Isomeric SMILES O=C(CNc1cccc2c1C(=O)N(C2=O)C1CCC(=O)NC1=O)NCCCCCCN1CCN(CC1)C(=O)c1ccc(cc1)Nc1nc(cn(c1=O)C)c1cccc(c1C)NC(=O)c1ccc(cc1)C(C)(C)C
InChI InChI=1S/C55H62N10O8/c1-34-39(12-10-14-41(34)60-49(68)35-16-20-37(21-17-35)55(2,3)4)43-33-62(5)54(73)48(59-43)58-38-22-18-36(19-23-38)51(70)64-30-28-63(29-31-64)27-9-7-6-8-26-56-46(67)32-57-42-15-11-13-40-47(42)53(72)65(52(40)71)44-24-25-45(66)61-50(44)69/h10-23,33,44,57H,6-9,24-32H2,1-5H3,(H,56,67)(H,58,59)(H,60,68)(H,61,66,69)
InChI Key QBPVFCNYKUENHU-UHFFFAOYSA-N
Bioactivity Comments
DD-03-171 promotes degradation of IKFZ1 and IKFZ3 (known cereblon neosubstrates) in addition to BTK [1]. It induces enhanced antiproliferative effects on mantle cell lymphoma (MCL) cells in vitro. Conjugating the parent kinase inhibitor to thalidomide did not alter its BTK inhibitory activity or its selectivity profile.
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Bruton tyrosine kinase Hs Inhibitor Inhibition 8.3 pIC50 - 1
pIC50 8.3 (IC50 5.1x10-9 M) [1]
Description: Inhibition of kinase activity in a biochemical assay.