KAT2A degrader-2
KAT2A degrader-2 is a selective molecular glue degrader targeting KAT2A, with a DC50 of 22 nM in Kelly cells. KAT2A degrader-2 acts as a molecular glue to recruit KAT2A to CRBN, forming a ternary complex that drives the polyubiquitination and proteasome-dependent degradation of KAT2A. KAT2A degrader-2 reduces the acetylation level of histone H3 lysine 9 via the ubiquitin-like and proteasome-dependent pathway. KAT2A degrader-2 can be used for the research of acute myeloid leukemia.
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- Formule: C31H36N8O5
- Masse moléculaire:600.67
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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KAT2A 22 nM (DC50) |
KAT2A degrader-2 (compound 4) potently and selectively mediates dimerization between CRBN and KAT2ANTD via a degron-independent interface involving KAT2A residue Y200, with a measured IC50 of 0.07 μM for wild-type KAT2ANTD displacement[1].
KAT2A degrader-2 (6 h) potently degrades endogenous KAT2A in Kelly cells with a DC50 of 22 nM and 90% maximum degradation after 6-hour treatment[1].
KAT2A degrader-2 (0.1-1 μM; 6 h) selectively degrades KAT2A over KAT2B, GSPT1, and GSPT2 in Kelly cells, functionally reducing H3K9Ac levels in a CRBN- and proteasome-dependent manner after 6-hour treatment[1].
KAT2A degrader-2 (1 μM; 6 h) exhibits exquisite proteome-wide selectivity, degrading only KAT2A in Kelly cells after 6-hour treatment with 1 μM[1].
KAT2A degrader-2 selectively recruits KAT2A to CRBN in Kelly cell lysates, with no other off-target proteins showing significant enrichment[1].
KAT2A degrader-2 (0.1-1 μM; 6 h) functionally inhibits KAT2A activity, reducing H3K9Ac levels in a CRBN- and proteasome-dependent manner in EOL-1 and MV4;11 AML cells after 6-hour treatment[1].
KAT2A degrader-2 (1 μM; 6 h) maintains exquisite proteome-wide selectivity, degrading only KAT2A in EOL-1 and MV4;11 AML cells after 6-hour treatment with 1 μM[1].
KAT2A degrader-2 (10-10-10-5 M; 9 days) exhibits context-specific antiproliferative activity in AML cell lines, with IC50 values ranging from 32.7 nM to 70.1 nM in KMT2A-rearranged sensitive lines and >10,000 nM in insensitive lines after 9-day treatment[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Kelly neuroblastoma cells
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Concentration:0.1-1 μM; 0.25 μM (combined with 1 μM MLN4924 or bortezomib)
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Incubation Time:6 h; 6 h (after MLN4924 or bortezomib pretreatment)
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Result:Induced dose-dependent degradation of KAT2A, with negligible degradation of the homologous KAT2B at doses >250 nM, and no degradation of GSPT1 or GSPT2 up to 1 μM.
Caused dose-dependent reduction of histone H3 lysine 9 acetylation (H3K9Ac), a primary KAT2A substrate.
Had its induced KAT2A degradation and H3K9Ac reduction blocked by pretreatment with the neddylation inhibitor MLN4924 or proteasome inhibitor bortezomib.
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Cell Line:MV4;11 (KMT2A::AFF1), EOL-1 (KMT2A partial tandem duplication), MOLM13 (KMT2A::MLLT3), MONOMAC6 (KMT2A::MLLT3), NB-4 (PML::RARA), NOMO1 (KMT2A::MLLT3), THP-1 (KMT2A::MLLT3)
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Concentration:10-10-10-5 M
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Incubation Time:9 days (with retreatment as needed)
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Result:Induced antiproliferative activity with IC50 = 32.7 nM in MV4;11 cells, IC50 = 40.6 nM in EOL-1 cells, IC50 = 37.3 nM in MOLM13 cells, and IC50 = 70.1 nM in MONOMAC6 cells.
Caused minimal sensitivity in NB-4, NOMO1, and THP-1 cells, with IC50 values >10,000 nM.
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Cell Line:EOL-1 and MV4;11 AML cell lines
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Concentration:0.1-1 μM; 0.25 μM (combined with 1 μM MLN4924 or bortezomib)
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Incubation Time:6 h; 6 h (after MLN4924 or bortezomib pretreatment)
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Result:Induced dose-dependent reduction of H3K9Ac in both EOL-1 and MV4;11 cells.
Had its induced H3K9Ac reduction blocked by pretreatment with MLN4924 or bortezomib, confirming dependence on neddylation and proteasome function.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Immunodeficient mice[1]
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Dosage:20 mg/kg
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Administration:s.c.; daily; 27 days
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Result:Improved median survival to 47.5 days.
Decreased human CD45+ leukemia burden in peripheral blood at days 26, 34, and 41.
Induced potent KAT2A degradation in harvested human CD45+ cells.
Reduced global H3K9Ac levels in harvested human CD45+ cells.
Caused no treatment-related changes in body weight or circulating blood cell counts.
Chemical Information
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Masse moléculaire 600.67
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Formule C31H36N8O5
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SMILES
O=C(N1)CCC(N2CC(C(NC3=C(N=CN4C5OCCCC5)C4=CC(N6CCN(C(C)(C)C)C6=O)=N3)=CC=C7)=C7C2=O)C1=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
KAT2A degrader-2 Related Classifications
HY-187169 Related Classifications
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