MA203
MA203 is a highly efficient and selective PROTAC degrader targeting CHK1. MA203 accelerates CRBN-dependent proteasomal degradation of CHK1 in solid tumor-derived cells and acute leukemia cells. MA203 induces DNA replication stress. MA203 blocks cell cycle progression and triggers tumor cell apoptosis. MA203 does not damage healthy differentiated and primitive hematopoietic cells, stromal cells, and retinal epithelial cells. MA203 can be used for the study of CHK1-dependent cancers.
(Pink: Chk1 ligand (HY-179158); Blue: Cereblon ligand (HY-41547); Black: linker (HY-22391)).
For research use only. We do not sell to patients.
- Formula: C38H45N9O8
- Molecular Weight:755.82
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
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Chk1 |
Bax |
Bcl-xL |
MA203 (PROTAC 41) reduces CHK1 levels by ∼50% at 5 µM in MIA PaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells and binds avidly to CHK1 (97% binding at 1.0 µM)[1].
MA203 (2 µM, 24 h) highly significantly attenuates CHK1 levels by up to 80% and 50% in Hydroxyurea (HY-B0313) (HU)-treated MIA PaCa-2 and MOLT-4 cells[1].
MA203 (2 μM, 3-24 h)-mediated CHK1 degradation is a time-dependent event accompanied by changes in phosphorylation state in MIA PaCa-2 cells, indicating that degradation enhances DNA damage signals[1].
MA203 plus HU reduces CHK1 significantly to 50 %-40 % of its levels in untreated cells in MOLT-4 cells, MOLM-13 cells, RS4-11 cells, HCT116 cells and attenuates CHK1 levels in MOLM-13 cells[1].
MA203 (1-5 µM, 24 h) dose-dependently attenuates CHK1 more efficiently when combined with 5 µM Irinotecan (HY-16562) than when used alone in MIA PaCa-2 cells[1].
MA203 (0.5-10 µM, 24 h) exhibits a significantly lower concentration for half-maximum CHK1 degradation when combined with 2 µM Cytarabine (HY-13605) (DC50 = 387.4 nM) than when used alone (DC50 = 3.86 µM) in MOLT-4 cells[1].
MA203 (0.5–10 μM, 24 h) enhances HU-induced DNA replication stress, leading to DNA double-strand breaks and replication catastrophe in MIA PaCa-2 and MOLT-4 cells[1].
MA203 (2 μM, 24-48 h) + HU significantly increases the proportion of cells undergoing early and late apoptosis in MIA PaCa-2 and MOLT-4 cells[1].
MA203 (2 µM, 24 h) alone and in combination with HU promotes the viability of dendritic cells[1].
MA203 (2 µM, 24 h) substantially augments Ara-C-mediated cell death, evidenced by a 62% decrease in the Ara-C concentration needed to kill 50% of MOLT-4 cells (IC50) in MOLT-4 cells[1].
MA203 (2 µM, 24 h) + HU for 24 h yields a unique and obvious reduction of several key proteins that control tumorigenesis and DNA damage repair, including transcription factor-7 (TCF7), cell division cycle-associated-7 (CDCA7), origin recognition complex subunit-1 (ORC1), and Werner syndrome RecQ-like helicase (WRN) and weakly augmented RRM2 levels in MIA PaCa-2 cells[1].
MA203 (2 µM, 24-48 h) + HU leads to stronger G1/S phase arrest; induces a higher apoptosis rate, accompanied by upregulation of BAX/BIM and downregulation of BCL-XL/XIAP; more significant loss of mitochondrial membrane potential and stronger caspase activation in MIA PaCa-2 cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:MIA PaCa-2 cells, MOLT-4 cells
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Concentration:2 µM
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Incubation Time:24 h
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Result:Specifically degraded CHK1, and this degradation is enhanced by HU-induced CHK1 activation.
Did not affect other checkpoint kinases or common CRBN substrates.
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Cell Line:MIA PaCa-2 cells
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Concentration:2 µM
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Incubation Time:3 h, 6 h, 10 h, 16 h, 24 h
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Result:Illustrated that the degradation of CHK1 started already after 3 h in MIA PaCa-2 cells, to yield a 50%-70% reduction of CHK1 after 10-16 h.
Suppressed the HU-induced hyperphosphorylation of CHK1 at S296 but augmented its HU-induced hyperphosphorylation at S345.
Did not alter CHK2 levels over different time points.
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Cell Line:MIA PaCa-2, MOLT-4
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Concentration:0.5 μM, 1 μM, 2 μM, 5 μM, 10μM
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Incubation Time:24 h
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Result:Significantly increased γH2AX levels (4.2-fold).
Achieved a Dmax of 92% at a DC50 of 1.51 µM in MIA PaCa-2 cells, and a Dmax of 93.2% at a DC50 of 5.35 µM in MOLT-4 cells.
Significant 15.7-fold induction of ATM phosphorylation at S1981.
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Cell Line:MIA PaCa-2 cells, HCT116 cells, MOLT-4 cells, MOLM-13 cells
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Concentration:2 μM
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Incubation Time:24 h, 48 h
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Result:After 48 h, the percentages of early and late apoptotic cells significantly increased to 15% and 14% in MIA PaCa-2 cell cultures; A significant rise in the early apoptotic cell population to 33% was observed.
In HCT116 cells, caused early and late apoptosis were significantly increased when combined with 0.5 mM HU for 48 h. An accumulation of late apoptotic cells (30%) occurred upon treatment.
Significantly augmented cell populations in early apoptosis to 19% and in late apoptosis to 15% after 24 h in MOLT-4 cells. In the presence of 1 mM HU, triggered early (48%) and late (24%) apoptotic cell death.
In MOLM-13 cells, triggered a significant accumulation of early apoptotic cells (33%), enhanced late apoptosis of MOLM-13 cells to 50%.
Normal human cells did not exhibit any significant impairment in viability upon treatment.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Chemical Information
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Molecular Weight 755.82
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Formula C38H45N9O8
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SMILES
O=C1CCC(N2C(C(C=CC=C3NCCCCCCCNC(C4=CC(OC[C@H]5OCCNC5)=C(NC(NC6=CN=C(C)C=N6)=O)C=C4)=O)=C3C2=O)=O)C(N1)=O
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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