Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C42H40N2O8 |
| Molecular Weight | 700.7756 |
| Optical Activity | UNSPECIFIED |
| Additional Stereochemistry | Yes |
| Defined Stereocenters | 2 / 2 |
| E/Z Centers | 0 |
| Charge | 0 |
| Stereo Comments | AXIAL, R |
SHOW SMILES / InChI
SMILES
C[C@@H](CNC(=O)C1=C(O)C(O)=CC2=C(O)C(=C(C)C=C12)C3=C(O)C4=C(C=C3C)C(C(=O)NC[C@H](C)C5=CC=CC=C5)=C(O)C(O)=C4)C6=CC=CC=C6
InChI
InChIKey=RAYNZUHYMMLQQA-ZEQRLZLVSA-N
InChI=1S/C42H40N2O8/c1-21-15-27-29(17-31(45)39(49)35(27)41(51)43-19-23(3)25-11-7-5-8-12-25)37(47)33(21)34-22(2)16-28-30(38(34)48)18-32(46)40(50)36(28)42(52)44-20-24(4)26-13-9-6-10-14-26/h5-18,23-24,45-50H,19-20H2,1-4H3,(H,43,51)(H,44,52)/t23-,24-/m0/s1
| Molecular Formula | C42H40N2O8 |
| Molecular Weight | 700.7756 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 2 / 2 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
Sabutoclax, an apogossypol derivative, also known as BI-97C1, functions as an inhibitor of all anti-apoptotic Bcl-2 proteins, including Bcl-XL, Bcl-2, Mcl-1, and Bfl-1. Sabutoclax induces cancer-specific cell death in a Mcl-1-dependent manner through both apoptosis and toxic mitophagy. Sabutoclax and COX-2 inhibitor, celecoxib, synergistically inhibit the growth of oral squamous cell carcinomas (OSCC) in vitro and significantly reduce OSCC tumor growth in vivo. These results identify Mcl-1 as a therapeutic prospective target in OSCC. Moreover, as shown, a combination regimen of tropism-modified adenovirus delivered mda-7/IL-24 (Ad.5/3-mda-7) and sabutoclax enhance cytotoxicity in human prostate cancer (PC) cells, including those resistant to mda-7/IL-24 or BI-97C1 alone, thus potentially augmenting the therapeutic benefit of this combinatorial approach toward PC.
CNS Activity
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: Q92934 Gene ID: 572.0 Gene Symbol: BAD Target Organism: Homo sapiens (Human) |
0.31 µM [IC50] | ||
Target ID: P10415 Gene ID: 596.0 Gene Symbol: BCL2 Target Organism: Homo sapiens (Human) |
0.32 µM [IC50] | ||
Target ID: Q07820|||Q9UHR8 Gene ID: 4170.0 Gene Symbol: MCL1 Target Organism: Homo sapiens (Human) |
0.2 µM [IC50] | ||
Target ID: Q16548 Gene ID: 597.0 Gene Symbol: BCL2A1 Target Organism: Homo sapiens (Human) |
0.62 µM [IC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
|||
| Primary | Unknown Approved UseUnknown |
PubMed
| Title | Date | PubMed |
|---|---|---|
| BI-97C1, an optically pure Apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. | 2010 May 27 |
|
| Sabutoclax, a Mcl-1 antagonist, inhibits tumorigenesis in transgenic mouse and human xenograft models of prostate cancer. | 2012 Jul |
|
| Mcl-1 is an important therapeutic target for oral squamous cell carcinomas. | 2015 Jun 30 |
Patents
Sample Use Guides
Nude mice xenograft model: FaDU-Luc (FaDU stably transfected with Luciferase) cells (2 × 106) were used to establish bilateral subcutaneous tumors on both flanks of 8–10 week old male athymic nude mice. Treatment began when tumors reached ~100-mm. Sabutoclax was administered at a dose of 3 mg/kg. Celecoxib was dissolved in PBS and administered at a dose of 50 mg/kg. Both drugs were given via I.P. injection three times per week (n = 5 mice / group) for four weeks. For in vivo imaging of tumors, the mice were anesthetized and injected I.P. with 150 mg/kg luciferin and light emitted from each tumor was determined using a Xenogen system with CCD camera with an integration time of 1 minute
Route of Administration:
Intraperitoneal
Assuming that Mcl-1 could function as a principal survival protein in OSCC; we treated human OSCC H357 cells with the Mcl-1 antagonist Sabutoclax in a dose-dependent manner (0-10 uM) for 48 hours and determined cell death. Sabutoclax induced cell death at a much lower dose as compared to ABT-737 in H357 cells. There also found increased levels of activated Bak with Sabutoclax treatment as compared to ABT-737 treatment. Sabutoclax-induced cancer-specific reduction in cell viability occurs in a Mcl-1-dependent manner.
| Substance Class |
Chemical
Created
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admin
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by
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Sat Dec 16 05:00:52 UTC 2023
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39Y89ZRK34
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