compound A [WO2022027058A1]   Click here for help

GtoPdb Ligand ID: 11904

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: This compound in an IRAK4 degrader (PROTAC) that is claimed in Kymera Therapeutics' patent WO2022027058A1 [1]. It is intended as a therapeutic for B-cell lymphomas that express oncogenic mutations in MYD88, e.g. the protein variant MYD88L265P. The cereblon binding portion of the molecule is based on the structure of the immunomodulatory imide drug (IMiD) lenalidomide. Compound A simultaneously promotes the degradation of IRAK4 and the zinc-finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), and this mechanism synergistically targets key pro-survival pathways in B-cell lymphomas (MYD88-NFκB and IRF4-Type 1 interferon) to enhance anti-tumour activity.
Kymera have an IRAK4/IMDi degrader (KT-413) in their clinical pipeline, but the name-to-structure has not been disclosed.
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 13
Hydrogen bond donors 4
Rotatable bonds 13
Topological polar surface area 202.17
Molecular weight 871.33
XLogP 4.66
No. Lipinski's rules broken 2
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Canonical SMILES O=C1CCC(C(=O)N1)N1C(=O)c2c(C1=O)cccc2NCCC1CC2(C1)CN(C2)C[C@@H]1CC[C@H](CC1)c1sc2c(n1)cc(c(c2)NC(=O)c1cccc(n1)C(F)(F)F)C(O)(C)C
Isomeric SMILES CC(C)(O)c1cc2c(sc(n2)[C@H]2CC[C@H](CN3CC4(CC(CCNc5c6C(=O)N(C7CCC(=O)NC7=O)C(=O)c6ccc5)C4)C3)CC2)cc1NC(=O)c1cccc(n1)C(F)(F)F
InChI InChI=1S/C45H48F3N7O6S/c1-43(2,61)28-17-32-34(18-31(28)51-38(57)30-7-4-8-35(50-30)45(46,47)48)62-40(52-32)26-11-9-24(10-12-26)21-54-22-44(23-54)19-25(20-44)15-16-49-29-6-3-5-27-37(29)42(60)55(41(27)59)33-13-14-36(56)53-39(33)58/h3-8,17-18,24-26,33,49,61H,9-16,19-23H2,1-2H3,(H,51,57)(H,53,56,58)/t24-,26-,33?
Classification Click here for help
Compound class Synthetic organic
Ligand families/groups PROTACs, molecular glues and other degraders
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Database Links Click here for help
GtoPdb PubChem SID 461663459
PubChem CID 156506667
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