product name A-1155463
Description: A-1155463, a highly potent and selective BCL-XL inhibitor that shows picomolar binding affinity to BCL-XL (Ki ＜0.01 nM), and >1000-fold weaker binding to BCL-2 (Ki = 80 nM) and related proteins BCL-W (Ki = 19 nM) and MCL-1 (Ki > 440 nM). A-1155463 represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization. [1] A-1155463 demonstratsstrong growth inhibition of over half of the colorectal cell lines as defined by EC50 values ≤0.5 μM in the presence of 10 % FBS.
References: ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93; Sci Transl Med. 2015 Mar 18;7(279):279ra40.
669.79
Formula
C35H32FN5O4S2
CAS No.
1235034-55-5
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 100 mg/mL (149.3 mM)
Water: <1 mg/mL
Ethanol: 100 mg/mL (149.3 mM)
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: A-1155463 disrupts BCL-XL-BIM but not BCL-2-BIM complexes in cells. A-1155463 kills BCL-XL-dependent Molt-4 cells (EC50=70 nM) but has no measurable cytotoxicity against BCL-2-dependent RS4;11 cells (EC50>5 mM). A-1155463 induces the hallmarks of apoptosis, as evidenced by the release of cytochrome c from mitochondria, caspase activation, and the accumulation of caspase-dependent sub-G0-G1 DNA content in BCL-XL-dependent H146 cells. Kinase Assay: A-1155463 is a highly potent and selective BCL-XL inhibitor, A-1155463 shows picomolar binding affinity to BCL-XL (Ki ＜0.01 nM), and >1000-fold weaker binding to BCL-2 (Ki = 80 nM) and related proteins BCL-W (Ki = 19 nM) and MCL-1 (Ki > 440 nM). Cell Assay: Cells are treated with increasing concentration of A-1155463. Cells are assayed for viability after 72 h using the CellTiter-Glo luminescent cell viability assay according to the manufacturer’s protocol. Results are normalized to cells without treatment. EC50 is calculated using the GraphPad Prism software. |
|---|---|
| In Vivo | A-1155463 causes a mechanism-based and reversible thrombocytopenia in mice and inhibits H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. he ability of A-1155463 to exert in vivo on-target activity was demonstrated through a rapid and reversible reduction in platelets in SCID-Beige mice following a single IP dose. Additionally, administration of A-1155463 to tumor bearing SCID-Beige mice afforded modest but statistically significant tumor growth inhibition. Detailed mechanistic studies of A-1155463 and combination activity with relevant chemotherapy across multiple tumor types will be reported in an accompanying manuscript. Following a single 5 mg/kg IP dose of A-1155463 in nontumor bearing SCID-Beige mice, platelet counts fall dramatically as measured at 6 h postdose and then rebound to normal levels within 72 h. Daily Dosing at 5 mg/kg IP to SCID-Beige mice that had been inoculated with BCL-XL-dependent H146 tumor cells for 14 days causes a statistically significant inhibition of tumor growth (maximum tumor growth inhibition = 44%), which is alleviated upon cessation of dosing. |
| Animal model | SCID-Beige Mice |
| Formulation & Dosage | Formulated in 5% DMSO, 10% EtOH, 20% Cremaphor ELP, and 65% D5W; 5 mg/kg; i.p. |
| References | ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93; Sci Transl Med. 2015 Mar 18;7(279):279ra40; Molecular Cancer. 2015, 14(1):1-9. |
