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YD54   Click here for help

GtoPdb Ligand ID: 13901

Compound class: Synthetic organic
Comment: YD54 is an orally bioavailable, cereblon-engaging PROTAC degrader of SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2 (SMARCA2) [3]. It is a bifunctional molecule containing a SMARCA2 bromodomain binding ligand linked to pomalidomide (to recruit the cereblon E3 ubiquitin ligase). Disrupting SMARCA2 is synthetic lethal in lung cancer cells that harbour loss of function mutations in the paralog SMARCA4 [1-2,4-5].
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Click here for structure editor
Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 15
Hydrogen bond donors 3
Rotatable bonds 10
Topological polar surface area 176.71
Molecular weight 763.82
XLogP 1.58
No. Lipinski's rules broken 2

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES C1=CC(=C(C=C1)O)C2=NN=C(C(=C2)N3CCN(CC3)CC4=CC=C(C(=C4)F)N5CCN(CC5)CCOC6=C7C(=CC=C6)C(=O)N(C8CCC(=O)NC8=O)C7=O)N
Isomeric SMILES O=C1N(C2CCC(NC2=O)=O)C(=O)C3=C1C(=CC=C3)OCCN4CCN(C5=C(F)C=C(CN6CCN(C7=C(N)N=NC(C8=C(O)C=CC=C8)=C7)CC6)C=C5)CC4
InChI InChI=1S/C40H42FN9O6/c41-28-22-25(24-47-14-18-49(19-15-47)32-23-29(44-45-37(32)42)26-4-1-2-6-33(26)51)8-9-30(28)48-16-12-46(13-17-48)20-21-56-34-7-3-5-27-36(34)40(55)50(39(27)54)31-10-11-35(52)43-38(31)53/h1-9,22-23,31,51H,10-21,24H2,(H2,42,45)(H,43,52,53)
InChI Key WBWCGTJXNCHFJI-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, Zollman D, Steurer S, Karolyi-Oezguer J, Riedmueller C et al.. (2019)
BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.
Nat Chem Biol, 15 (7): 672-680. [PMID:31178587]
2. Hoffman GR, Rahal R, Buxton F, Xiang K, McAllister G, Frias E, Bagdasarian L, Huber J, Lindeman A, Chen D et al.. (2014)
Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers.
Proc Natl Acad Sci U S A, 111 (8): 3128-33. [PMID:24520176]
3. Kotagiri S, Wang Y, Han Y, Liang X, Blazanin N, Mazhar H, Sebastian M, Nguyen PK, Jiang Y, Lissanu Y. (2025)
Discovery of Novel, Potent, and Orally Bioavailable SMARCA2 Proteolysis-Targeting Chimeras with Synergistic Antitumor Activity in Combination with Kirsten Rat Sarcoma Viral Oncogene Homologue G12C Inhibitors.
J Med Chem, 68 (9): 9202-9219. [PMID:40280558]
4. Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, Mizukami T, Shimada Y, Isomura H, Komachi M et al.. (2013)
A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1.
Cancer Res, 73 (17): 5508-18. [PMID:23872584]
5. Rago F, DiMare MT, Elliott G, Ruddy DA, Sovath S, Kerr G, Bhang HC, Jagani Z. (2019)
Degron mediated BRM/SMARCA2 depletion uncovers novel combination partners for treatment of BRG1/SMARCA4-mutant cancers.
Biochem Biophys Res Commun, 508 (1): 109-116. [PMID:30527810]