2. Cell Cycle/DNA Damage Apoptosis
  3. DNA Alkylator/Crosslinker DNA/RNA Synthesis Apoptosis
  4. SY-589

SY-589 is an orally active DNA polymerase Polθ helicase domain inhibitor (IC50=2.29 nM) and DNA damage inducer. SY-589 inhibits the ATPase activity of the Polθ helicase domain and blocks the Polθ-mediated microhomology-mediated end joining (MMEJ) DNA repair pathway (IC50=0.85 nM). SY-589 also induces the accumulation of DNA double-strand breaks by increasing γ-H2AX levels. SY-589 exerts antiproliferative effects on BRCA2-deficient cells and is used in the research of HR-deficient tumors.

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SY-589

SY-589 Chemical Structure

CAS No. : 3077714-09-8

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Description

SY-589 is an orally active DNA polymerase Polθ helicase domain inhibitor (IC50=2.29 nM) and DNA damage inducer. SY-589 inhibits the ATPase activity of the Polθ helicase domain and blocks the Polθ-mediated microhomology-mediated end joining (MMEJ) DNA repair pathway (IC50=0.85 nM). SY-589 also induces the accumulation of DNA double-strand breaks by increasing γ-H2AX levels. SY-589 exerts antiproliferative effects on BRCA2-deficient cells and is used in the research of HR-deficient tumors[1].

IC50 & Target

DNA Polymerase

 

Helicase

 

In Vitro

SY-589 (administered on days 0, 3, and 6) potently inhibits the viability of homologous recombination-deficient DLD1 BRCA2-/- colon cancer cells, with an IC50 of 2.71 nM[1].
SY-589 (0.05-12.8 nM; 10 d) induces dose-dependent accumulation of DNA double-strand breaks (detected by γ-H2AX levels) in DLD1 BRCA2-/- cells, and exerts dose-dependent effects on inhibiting colony formation, inducing cell cycle arrest and triggering apoptosis in DLD1 BRCA2-/- cells[1].
SY-589 (0.39-100 nM; 10 d) exerts strong synergistic effects with the PARP inhibitor Olaparib (HY-10162) to inhibit the viability of DLD1 BRCA2-/- cells, and significantly enhances the antiproliferative activity of Olaparib[1].

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

SY-589 Related Antibodies

Western Blot Analysis[1]

Cell Line: DLD1 BRCA2-/- cells
Concentration: 0.05, 0.2, 0.8, 3.2, 12.8 nM
Incubation Time: 10 days
Result: Induced a dose-dependent increase in γ-H2AX protein levels (a biomarker of DNA double-strand breaks), with the highest fold change observed at 12.8 nM.

Apoptosis Analysis[1]

Cell Line: DLD1 BRCA2-/- cells
Concentration: 0.05, 0.8, 12.8 nM
Incubation Time: 10 days (medium refreshed every 2 days)
Result: Induced dose-dependent changes in cell cycle distribution, increasing the S-phase population from 18.12% (control) to 28.33% at 12.8 nM.
Induced apoptosis in a dose-dependent manner, with the apoptotic rate increasing from 9.13% (control) to 34.2% at 12.8 nM.

Cell Proliferation Assay[1]

Cell Line: DLD1 BRCA2-/- cells
Concentration: 0.05, 0.2, 0.8, 3.2, 12.8 nM
Incubation Time: 12 days (medium refreshed every 2 days)
Result: Suppressed colony formation in a dose-dependent manner, with complete suppression observed at 12.8 nM.

Cell Proliferation Assay[1]

Cell Line: DLD1 BRCA2-/- cells
Concentration: 0.39, 1.56, 6.25, 25, 100 nM (SY-589); serially diluted (Olaparib)
Incubation Time: 10 days (dosed on day 0, day 3, day 6)
Result: Exhibited strong synergistic antiproliferative activity with Olaparib, with a Loewe synergy score of >20.
Enhanced the antiproliferative effect of Olaparib, shifting from no suppression to >50% suppression of cell proliferation when paired with low-dose Olaparib (0.15 nM).
Parmacokinetics
Species Dose Route T1/2 Tmax Cmax AUC0-t AUC0-∞ MRT0-t MRT0-∞ Vss CL F
Mice[1] 2 mg/kg i.v. 1.38 h 0.08 h 6661.55 ng/mL 11178.99 ng·h/mL 11454.79 ng·h/mL 1.51 h 1.70 h 0.30 L/kg 2.95 mL/min/kg /
Mice[1] 30 mg/kg p.o. 2.51 h 0.58 h 44547.59 ng/mL 185078.88 ng·h/mL 185274.47 ng·h/mL 4.00 h 4.02 h / / 107.83 %
In Vivo

SY-589 (0.5-30 mg/kg; p.o.; daily; 27 d) inhibits tumor growth in the DLD1BRCA2-/- xenograft model; when combined with low-dose Olaparib (HY-10162), the tumor growth inhibition (TGI) rate reaches up to 109% with no significant toxicity[1].

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

Animal Model: BALB/c nude mice with Colorectal cancer (female, 6-8 weeks old)[1]
Dosage: 30 mg/kg (monotherapy TGI); 0.5 mg/kg (combination 99% TGI); 2.5 mg/kg (combination 107% TGI); 12.5 mg/kg (combination 109% TGI)
Administration: p.o.; daily; 27 days
Result: Achieved 59% tumor growth inhibition (TGI) as monotherapy.
Achieved 99% TGI in combination with 25 mg/kg Olaparib.
Achieved 107% TGI with marked tumor regression in combination with 25 mg/kg Olaparib.
Achieved 109% TGI with marked tumor regression in combination with 25 mg/kg Olaparib.
Caused no significant body weight changes in any treatment group during the study.
Molecular Weight

552.97

Formula

C24H18ClFN8O3S
CAS No.
SMILES

COC1=C(C=C(Cl)N=C1)C2=CC(N3C(C(F)=CC=C3)=O)=NC=C2C(NC4=NC(C5=C(C=NN5C)C)=NS4)=O
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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SY-589 Related Classifications

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Help & FAQs
  • 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:

SY-5893077714-09-8SY589SY 589DNA Alkylator/CrosslinkerDNA/RNA SynthesisApoptosisATPase activityhuman Polθ helicase domainmicro-homology-mediated end joiningHR-deficient tumorsDLD1 BRCA2-/- colon cancer cellshomologous recombination-deficient cellsDNA polymerase theta helicase domainBRCA2-deficient cellsγ-H2AXDNA double-strand breaksInhibitorinhibitorinhibit

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