2. PROTAC Apoptosis Cell Cycle/DNA Damage JAK/STAT Signaling Protein Tyrosine Kinase/RTK Metabolic Enzyme/Protease Vitamin D Related/Nuclear Receptor
  3. Molecular Glues Bcl-2 Family CDK EGFR HSP Androgen Receptor c-Myc
  4. XYD049

XYD049 is a CRBN-based molecular glue degrader targeting GSPT1, with a DC50 of 19 nM. XYD049 mediates the formation of a ternary complex between CRBN and GSPT1, thereby triggering CRBN- and proteasome-dependent degradation of GSPT1. By degrading GSPT1, XYD049 downregulates castration-resistant prostate cancer (CRPC)-related oncogenes, including BCL2, CDK2, E2F3, EGFR, HSP90B1, TMPRSS2, AR, AR-V7, PSA and c-Myc. XYD049 inhibits cancer cell growth and suppresses tumor growth in mice. XYD049 can be used for research on castration-resistant prostate cancer. XYD049 consists of a linker (black part) NH2-C5-NH-Boc (HY-W004710), a CRBN-based E3 ligase ligand (blue part) Thalidomide 4-fluoride (HY-41547), and a target protein ligand (red part) GSPT1 ligand-1 (HY-170821), among which the E3 ligase ligand plus linker forms the conjugate E3 Ligase Ligand-linker Conjugate 158 (HY-170822).

For research use only. We do not sell to patients.

XYD049

XYD049 Chemical Structure

CAS No. : 3006788-11-7

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Based on 1 publication(s) in Google Scholar

XYD049 Related Antibodies

Top Publications Citing Use of Products

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HSP40 HSP70 HSP90 HSP105 HSF1 HSP HSPA5

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Description

XYD049 is a CRBN-based molecular glue degrader targeting GSPT1, with a DC50 of 19 nM. XYD049 mediates the formation of a ternary complex between CRBN and GSPT1, thereby triggering CRBN- and proteasome-dependent degradation of GSPT1. By degrading GSPT1, XYD049 downregulates castration-resistant prostate cancer (CRPC)-related oncogenes, including BCL2, CDK2, E2F3, EGFR, HSP90B1, TMPRSS2, AR, AR-V7, PSA and c-Myc. XYD049 inhibits cancer cell growth and suppresses tumor growth in mice. XYD049 can be used for research on castration-resistant prostate cancer. XYD049 consists of a linker (black part) NH2-C5-NH-Boc (HY-W004710), a CRBN-based E3 ligase ligand (blue part) Thalidomide 4-fluoride (HY-41547), and a target protein ligand (red part) GSPT1 ligand-1 (HY-170821), among which the E3 ligase ligand plus linker forms the conjugate E3 Ligase Ligand-linker Conjugate 158 (HY-170822)[1].

IC50 & Target[1]

CDK2

 

Bcl-2

 

HSP90AB1

 

In Vitro

XYD049 (Compound 7d) (0.1 nM-20 μM; 96 h) potently inhibits the proliferation of LNCaP, 22Rv1 and C4-2B cells, with the strongest inhibitory activity against 22Rv1 cells (IC50 = 0.007 μM)[1].
XYD049 (6.25-25 nM; 14 days) potently inhibits colony formation of 22Rv1 cells[1].
XYD049 (12-1000 nM; 1-18 h) potently induces dose- and time-dependent degradation of GSPT1 in 22Rv1 castration-resistant prostate cancer cells, with a DC50 of 19 nM[1].
XYD049 (500 nM; 6 h) allows the gradual recovery of GSPT1 protein levels in 22Rv1 cells after washout[1].
Degradation of GSPT1 induced by XYD049 (500 nM; 6 h, with 2 h pretreatment of 500 nM MG132 (HY-13259) or PS-341 (HY-10227)) in 22Rv1 castration-resistant prostate cancer cells depends on the proteasome pathway[1].
Degradation of GSPT1 in castration-resistant 22Rv1 prostate cancer cells induced by XYD049 (300 nM-500 nM; 6 h) depends on binding to CRBN[1].
XYD049 (0.12-3.33 μM) forms the DDB1ΔBPB-CRBNΔ40-XYD049 binary complex, which binds to GSPT1 in vitro with a Kd value of 0.93 μM[1].
XYD049 (0.1 nM-20 μM; 1.5 h at room temperature) potently promotes the formation of a ternary complex between GSPT1 and CRBN in vitro[1].
XYD049 (0-1000 nM; 12 h) downregulates the mRNA expression of BCL2, CDK2, E2F3, EGFR, HSP90B1, TMPRSS2, AR-FL, AR-V7, KLK3 and c-Myc, and reduces the protein expression levels of AR-FL, AR-V7, KLK3, c-Myc, BCL2, BCL-XL and MCL-1[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

XYD049 Related Antibodies

Cell Viability Assay[1]

Cell Line: castration-resistant prostate cancer (CRPC) cell lines LNCaP, 22Rv1, and C4-2B
Concentration: 0.1 nM, 10 nM, 1 μM, 20 μM
Incubation Time: 96 h
Result: Inhibited proliferation of LNCaP cells with an IC50 of 0.034 μM.
Inhibited proliferation of 22Rv1 cells with an IC50 of 0.007 μM.
Inhibited proliferation of C4-2B cells with an IC50 of 0.374 μM.
Was ~200-fold more potent than BET PROTAC degrader 5 (dBET1) in 22Rv1 cells.
Was more potent than GSPT1 degrader 1 (CC-90009) in 22Rv1 cells.

Cell Migration Assay [1]

Cell Line: 22Rv1 cells
Concentration: 6.25, 12.5, 25 nM
Incubation Time: 14 days
Result: Potently suppressed colony formation of 22Rv1 CRPC cells at concentrations as low as 6.25 nM.

Western Blot Analysis[1]

Cell Line: 22Rv1 CRPC cells
Concentration: 12, 37, 111, 333, 1000 nM (6 h or 18 h incubation); 300 nM (1-6 h incubation)
Incubation Time: 6 h, 18 h, 1 h, 2 h, 4 h
Result: Induced dose- and time-dependent degradation of GSPT1 in 22Rv1 cells, with a DC50 of 19 nM.
Exhibited faster onset of GSPT1 downregulation than GSPT1 degrader 1 (CC-90009).

Western Blot Analysis[1]

Cell Line: 22Rv1 CRPC cells
Concentration: 500 nM
Incubation Time: 6 h, followed by washout and incubation for 0-72 h
Result: GSPT1 protein levels gradually recovered over time after removal of XYD049.

Western Blot Analysis[1]

Cell Line: 22Rv1 CRPC cells
Concentration: 500 nM MG132 or PS-341 (pretreatment); 500 nM XYD049
Incubation Time: 2 h pretreatment, followed by 6 h incubation
Result: Pretreatment with MG132 or PS-341 abolished the XYD049-induced reduction of GSPT1 protein levels.

Western Blot Analysis[1]

Cell Line: 22Rv1 CRPC cells
Concentration: 1-5 μM pomalidomide (HY-10984) (pretreatment); 300 nM XYD049; 100 nM siCRBN-1 or siCRBN-2 (transfection); 500 nM XYD049
Incubation Time: 2 h pretreatment, followed by 6 h incubation; 48 h transfection, followed by 6 h incubation
Result: Pretreatment with pomalidomide attenuated XYD049-induced GSPT1 degradation.
CRBN silencing abolished the XYD049-induced GSPT1 degradation effect.
In Vivo

XYD049 (10-20 mg/kg; i.p.; once daily; for 21 consecutive days) induces dose-dependent tumor growth inhibition in 22Rv1 castration-resistant prostate cancer xenografts[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: NOD-SCID (4 weeks old, 17−20 g; injected subcutaneously with 3×106 22Rv1 tumor cells)[1]
Dosage: 10 mg/kg; 20 mg/kg
Administration: i.p.; daily; 21 days
Result: Achieved a tumor growth inhibition (TGI) of 44%.
Achieved a tumor growth inhibition (TGI) of 55%.
Exhibited good tolerability in mice, as monitored by body weight changes.
Molecular Weight

811.66

Formula

C35H35BrN6O10S
CAS No.
Appearance

Solid

Color

Light yellow to yellow

SMILES

CC1=NOC2=CC(OCC(NCCCCCNC3=CC=CC(C(N4C5CCC(NC5=O)=O)=O)=C3C4=O)=O)=C(C=C21)NS(C6=C(C=CC(Br)=C6)OC)(=O)=O
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : 50 mg/mL (61.60 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 1.2320 mL 6.1602 mL 12.3204 mL
5 mM 0.2464 mL 1.2320 mL 2.4641 mL
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

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Purity & Documentation
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.2320 mL 6.1602 mL 12.3204 mL 30.8011 mL
5 mM 0.2464 mL 1.2320 mL 2.4641 mL 6.1602 mL
10 mM 0.1232 mL 0.6160 mL 1.2320 mL 3.0801 mL
15 mM 0.0821 mL 0.4107 mL 0.8214 mL 2.0534 mL
20 mM 0.0616 mL 0.3080 mL 0.6160 mL 1.5401 mL
25 mM 0.0493 mL 0.2464 mL 0.4928 mL 1.2320 mL
30 mM 0.0411 mL 0.2053 mL 0.4107 mL 1.0267 mL
40 mM 0.0308 mL 0.1540 mL 0.3080 mL 0.7700 mL
50 mM 0.0246 mL 0.1232 mL 0.2464 mL 0.6160 mL
60 mM 0.0205 mL 0.1027 mL 0.2053 mL 0.5134 mL
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XYD049 Related Classifications

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  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

XYD0493006788-11-7XYD 049XYD-049Molecular GluesBcl-2 FamilyCDKEGFRHSPAndrogen Receptorc-MycCyclin dependent kinaseEpidermal growth factor receptorErbB-1HER1Heat shock proteinsMycAR-V7GSPT1castration-resistant prostate cancerCRBNproteasomeC4-2BLNCaP22Rv1ARPSAInhibitorinhibitorinhibit

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