THAL-SNS-032   Click here for help

GtoPdb Ligand ID: 10547

Compound class: Synthetic organic
Comment: THAL-SNS-032 is a cereblon (CRBN)-engaging degrader of the CDK9 kinase protein [1]. It is a bifunctional molecule that simultaneously engages the CDK protein (via the multi-targeting kinase inhibitor BMS-387032, a.k.a. SNS-032) and cereblon (via a thalidomide derivative) to promote E3 ligase-mediated ubiquitination and proteasomal degradation of the target CDK. Hybrid molecules with this action can be described as PROTACs (proteolysis targeting chimeras).
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 17
Hydrogen bond donors 4
Rotatable bonds 24
Topological polar surface area 277.17
Molecular weight 868.32
XLogP -1.16
No. Lipinski's rules broken 2
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Canonical SMILES O=C(CN1CCC(CC1)C(=O)Nc1ncc(s1)SCc1ncc(o1)C(C)(C)C)NCCOCCOCCOCCNc1cccc2c1C(=O)N(C2=O)C1CCC(=O)NC1=O
Isomeric SMILES O=C(CN1CCC(CC1)C(=O)Nc1ncc(s1)SCc1ncc(o1)C(C)(C)C)NCCOCCOCCOCCNc1cccc2c1C(=O)N(C2=O)C1CCC(=O)NC1=O
InChI InChI=1S/C40H52N8O10S2/c1-40(2,3)29-21-43-32(58-29)24-59-33-22-44-39(60-33)46-35(51)25-9-13-47(14-10-25)23-31(50)42-12-16-56-18-20-57-19-17-55-15-11-41-27-6-4-5-26-34(27)38(54)48(37(26)53)28-7-8-30(49)45-36(28)52/h4-6,21-22,25,28,41H,7-20,23-24H2,1-3H3,(H,42,50)(H,44,46,51)(H,45,49,52)
Bioactivity Comments
THAL-SNS-032 selectively degrades CDK9 in vitro. Partial degradation of CDK10 was detected (but only following prolongued exposure), despite this being an unreported target of SNS-032. THAL-SNS-032 does not degrade other SNS-032-targeted kinases. Kinase profile screening showed that modifying the parent kinase inhibitor to add the linker for THAL-SNS-032 did not alter its selectivity profile [1].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
cyclin dependent kinase 9 Hs Inhibitor Inhibition 8.4 pIC50 - 1
pIC50 8.4 (IC50 4x10-9 M) [1]
Description: Biochemical inhibition of CDK9/CycT1.
cyclin dependent kinase 2 Hs Inhibitor Inhibition 7.2 pIC50 - 1
pIC50 7.2 (IC50 6.2x10-8 M) [1]
Description: Biochemical inhibition of CDK2/cyclin A
cyclin dependent kinase 1 Hs Inhibitor Inhibition 6.8 pIC50 - 1
pIC50 6.8 (IC50 1.71x10-7 M) [1]
Description: Biochemical inhibition of CDK1/CycB.
cyclin dependent kinase 7 Hs Inhibitor Inhibition 6.4 pIC50 - 1
pIC50 6.4 (IC50 3.98x10-7 M) [1]
Description: Inhibition of CDK7/CycH/MNAT1.