2. PROTAC PI3K/Akt/mTOR Cell Cycle/DNA Damage Apoptosis
  3. PROTACs ATM/ATR Checkpoint Kinase (Chk) Apoptosis DNA/RNA Synthesis Caspase Bcl-2 Family MDM-2/p53
  4. PROTAC ATR degrader-3

PROTAC ATR degrader-3 is a potent CRBN-based ATR PROTAC degrader with a DC50 of 127 nM. PROTAC ATR degrader-3 also degrades CHK1 with an DC50 of 135 nM. PROTAC ATR degrader-3 inhibits cancer cells proliferation, migration and invasion, triggers apoptosis and induces S phase arrest and DNA damage. PROTAC ATR degrader-3 achieves tumor growth inhibition in LoVo xenograft mouse model without apparent toxicity. PROTAC ATR degrader-3 can be used for the research of colorectal cancer.
(Pink: ATR ligand (HY-182017); Blue: Cereblon ligand (HY-W077589A); Black: linker).

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

PROTAC ATR degrader-3

PROTAC ATR degrader-3 Chemical Structure

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PROTAC ATR degrader-3 Related Antibodies

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von Hippel-Lindau (VHL) Cereblon MDM2 cIAP1

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ATM ATR TRRAP

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RNASE L DNA Polymerases RNA Polymerases Helicases DNA Ligase

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Bcl-2 Bcl-xL Bcl-W Mcl-1 Bfl-1 Bcl-B Bax Bak Bim BNIP3 Bad

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Description

PROTAC ATR degrader-3 is a potent CRBN-based ATR PROTAC degrader with a DC50 of 127 nM. PROTAC ATR degrader-3 also degrades CHK1 with an DC50 of 135 nM. PROTAC ATR degrader-3 inhibits cancer cells proliferation, migration and invasion, triggers apoptosis and induces S phase arrest and DNA damage. PROTAC ATR degrader-3 achieves tumor growth inhibition in LoVo xenograft mouse model without apparent toxicity. PROTAC ATR degrader-3 can be used for the research of colorectal cancer[1]. (Pink: ATR ligand (HY-182017); Blue: Cereblon ligand (HY-W077589A); Black: linker).

IC50 & Target[1]

Cereblon

 

ATR

127 nM (DC50)

Chk1

135 nM (DC50)

Caspase 3

 

Bcl-2

 

In Vitro

PROTAC ATR degrader-3 (Compound A12) potently and selectively inhibits ATR kinase in cell-free assays with an IC50 of 2.7 ± 0.5 nM, showing minimal activity against DNA-PK, PI3Kα, and ATM[1].
PROTAC ATR degrader-3 (31 nM-5 μM; 8-72 h) induces potent, time- and concentration-dependent proteasome-mediated degradation of ATR in LoVo cells with a DC50 of 127 nM and Dmax of 72% after 72 h[1].
PROTAC ATR degrader-3 (72 h) induces potent degradation of ATR in SW480 (DC50 = 140 nM, Dmax = 95%) and HCT116 (DC50 = 48 nM, Dmax = 77%) colorectal cancer cells[1].
PROTAC ATR degrader-3 (0-10 μM; 16-72 h) induces potent, concentration-dependent proteasome-mediated degradation of CHK1 in LoVo cells with a DC50 of 135 nM and Dmax of 70% after 72 h[1].
PROTAC ATR degrader-3 (72 h) induces degradation of CHK1 in SW480 (DC50 = 426 nM, Dmax = 90%) and HCT116 (DC50 = 95 nM, Dmax = 74%) colorectal cancer cells[1].
PROTAC ATR degrader-3 (serial concentrations; 72 h) potently inhibits the proliferation of LoVo colorectal cancer cells with an IC50 of 0.055 ± 0.010 μM, showing lower activity against SW480 (IC50 = 0.37 μM), HCT116 (IC50 = 2.774 μM), and normal NCM460 (IC50 = 13.161 μM) cells[1].
PROTAC ATR degrader-3 (250 nM; 48 h, with 2 μM MG132 co-treatment) enhances ATR polyubiquitination in LoVo cells, confirming ubiquitin-dependent proteasomal degradation[1].
PROTAC ATR degrader-3 (0.5-2.0 μM; 48 h) induces S-phase cell cycle arrest in LoVo cells after 48 h of treatment, with maximum S-phase population of 38.05% at 1.0 μM[1].
PROTAC ATR degrader-3 (0.5-4.0 μM; 48 h) dose-dependently induces apoptosis in LoVo cells by activation of caspase-mediated apoptotic pathways[1].
PROTAC ATR degrader-3 (0.5-2.0 μM; 10 days) potently and dose-dependently suppresses colony formation of LoVo cells over 10 days[1].
PROTAC ATR degrader-3 (0.5-2.0 μM; 24-48 h) dose-dependently inhibits the migration and invasion of LoVo cells[1].
PROTAC ATR degrader-3 (0.5-4.0 μM; 24 h) induces dose-dependent DNA damage accumulation in LoVo cells, accompanied by increased γH2AX expression[1].

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

PROTAC ATR degrader-3 Related Antibodies

Western Blot Analysis[1]

Cell Line: LoVo human colorectal cancer cells
Concentration: 31, 62, 125. 250, 500, 1000, 2000, 5000 nM
Incubation Time: 8, 16, 24, 48, 72 h
Result: Induced 60 ± 5% ATR degradation at 0.1 μM and 78 ± 3% degradation at 0.5 μM after 72 h.
Achieved a DC50 of 127 nM and maximum degradation (Dmax) of 72% after 72 h.
Induced significant ATR degradation at 250 nM by 48 h.
Blocked ATR degradation when cells were pre-treated with MG132 (HY-13259) or lenalidomide.

Western Blot Analysis[1]

Cell Line: LoVo human colorectal cancer cells
Concentration: 0-10000 nM (72 h); 1 μM (16 h, with 2 h pre-incubation with 2 μM MG132, 2 μM lenalidomide, or 2 μM C1); 0.5-4 μM (24 h)
Incubation Time: 16 h (with pre-treatment); 24 h; 72 h
Result: Induced concentration-dependent CHK1 degradation with a DC50 of 135 nM and Dmax of 70% after 72 h.
Blocked CHK1 degradation when cells were pre-treated with MG132 or lenalidomide.
Reduced CHK1 protein levels at concentrations ≥0.5 μM after 24 h.

Western Blot Analysis[1]

Cell Line: LoVo human colorectal cancer cells
Concentration: 250 nM (with 2 μM MG132 co-treatment)
Incubation Time: 48 h
Result: Markedly enhanced polyubiquitination of ATR protein, as shown by increased ubiquitin signal in immunoprecipitated ATR samples.

Cell Cycle Analysis[1]

Cell Line: LoVo human colorectal cancer cells
Concentration: 0.5, 1.0, 2.0, 4.0 μM
Incubation Time: 48 h
Result: Induced S-phase arrest: 35.30% of cells in S-phase at 0.5 μM, 38.05% at 1.0 μM, 37.65% at 2.0 μM, compared to 29.11% in control cells.
Reduced G0-G1 phase population to 53.69% (0.5 μM), 50.79% (1.0 μM), 51.80% (2.0 μM), compared to 58.66% in control cells.

Apoptosis Analysis[1]

Cell Line: LoVo human colorectal cancer cells
Concentration: 0.5-2.0 μM
Incubation Time: 48 h
Result: Induced dose-dependent apoptosis.
Increased levels of cleaved PARP1 and cleaved Caspase-3 in a concentration-dependent manner.
Reduced Bcl-2 levels.
In Vivo

PROTAC ATR degrader-3 (Compound A12) (10-30 mg/kg; i.p.; twice daily; 32 days) demonstrates dose-dependent, significant suppression of LoVo colorectal cancer xenograft growth in nude mice, with a maximum TGI of 74% at 30 mg/kg, without adverse effects on body weight[1].

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

Animal Model: Nude mice with LoVo colorectal cancer xenograft (female, 7-8 weeks old)[1]
Dosage: 10, 20, 30 mg/kg; 10 mg/kg (combination with Cetuximab)
Administration: i.p.; twice daily; 32 days; i.v. (cetuximab, every 4 days)
Result: Achieved 43% tumor growth inhibition (TGI) at 10 mg/kg monotherapy.
Achieved 57% TGI at 20 mg/kg monotherapy.
Achieved 74% TGI at 30 mg/kg monotherapy.
Achieved 81% TGI at 10 mg/kg in combination with Cetuximab (HY-P9905).
Caused no adverse effect on mouse body weight.
Downregulated ATR, p-ATR, CHK1, and p-CHK1 expression in tumor tissue.
Upregulated p-p53, p21, and γH2AX expression in tumor tissue.
Molecular Weight

738.79

Formula

C41H38N8O6
SMILES

C[C@@H]1COCCN1C2=C3C(CN(C3)C(C4=CC=C(C=C4)C(NCC5=CC=C6C(CN(C6=O)C7C(NC(CC7)=O)=O)=C5)=O)=O)=NC(C8=CC=CC9=C8C=CN9)=N2
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Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
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PROTAC ATR degrader-3 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:

PROTAC ATR degrader-3PROTAC ATR degrader3PROTAC ATR degrader 3PROTACsATM/ATRCheckpoint Kinase (Chk)ApoptosisDNA/RNA SynthesisCaspaseBcl-2 FamilyMDM-2/p53Ataxia telangiectasia mutatedATM and RAD3 relatedLoVo xenograft mouse modelLoVo cellscolorectal cancer cellsNCM460 cellsCHK1ATRproteasomal degradationHCT116 cellsapoptosisSW480 cellsInhibitorinhibitorinhibit

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