A-1210477 - CAS 1668553-26-1
Catalog number: 1668553-26-1
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C46H55N7O7S
Molecular Weight:
850.04
COA:
Inquire
Targets:
Bcl-2 Family
Description:
A-1210477 is a potent and selective MCL-1 inhibitor with Ki and IC50 of 0.454 nM and 26.2 nM, respectively, >100-fold selectivity over other Bcl-2 family members.
Purity:
98%
Appearance:
Solid powder
Synonyms:
A 1210477; A1210477.
Solubility:
DMSO,6mg/mLwarmed(7.05mM);Water,<1mg/mL(<1mM);Ethanol,<1mg/mL(<1mM)
Storage:
3 years -20℃powder;6 months-80℃in solvent
MSDS:
Inquire
Shelf Life:
2 years if stored properly
Canonical SMILES:
O=C(C(N1CCN2CCOCC2)=C(CCCOC3=C(C=CC=C4)C4=CC=C3)C5=C1C(C6=C(COC7=CC=C(N8CCN(S(=O)(N(C)C)=O)CC8)C=C7)N(C)N=C6C)=CC=C5)O
1.MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor.
Xiao Y;Nimmer P;Sheppard GS;Bruncko M;Hessler P;Lu X;Roberts-Rapp L;Pappano WN;Elmore SW;Souers AJ;Leverson JD;Phillips DC Mol Cancer Ther. 2015 Aug;14(8):1837-47. doi: 10.1158/1535-7163.MCT-14-0928. Epub 2015 May 26.
Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt of signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted to the BCL-2 family proteins for survival are now being targeted therapeutically. For example, navitoclax, a BCL-2/BCL-XL/BCL-W inhibitor, is currently in phase I/II clinical trials in numerous malignancies. However, the related family member, MCL-1, limits the efficacy of navitoclax and other chemotherapeutic agents. In the present study, we identify breast cancer cell lines that depend upon MCL-1 for survival and subsequently determine the mechanism of apoptosis mediated by the MCL-1 selective inhibitor A-1210477. We demonstrate that apoptosis resulting from a loss in MCL-1 function requires expression of the proapoptotic protein BAK. However, expression of BCL-XL can limit apoptosis resulting from loss in MCL-1 function through sequestration of free BIM. Finally, we demonstrate substantial synergy between navitoclax and MCL-1 siRNA, the direct MCL-1 inhibitor A-1210477, or the indirect MCL-1 inhibitor flavopiridol, highlighting the therapeutic potential for inhibiting BCL-XL and MCL-1 in breast cancer.
2.Systems modeling accurately predicts responses to genotoxic agents and their synergism with BCL-2 inhibitors in triple negative breast cancer cells.
Lucantoni F;Lindner AU;O'Donovan N;Düssmann H;Prehn JHM Cell Death Dis. 2018 Jan 19;9(2):42. doi: 10.1038/s41419-017-0039-y.
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer which accounts for 15-20% of this disease and is currently treated with genotoxic chemotherapy. The BCL2 (B-cell lymphoma 2) family of proteins controls the process of mitochondrial outer membrane permeabilization (MOMP), which is required for the activation of the mitochondrial apoptosis pathway in response to genotoxic agents. We previously developed a deterministic systems model of BCL2 protein interactions, DR_MOMP that calculates the sensitivity of cells to undergo mitochondrial apoptosis. Here we determined whether DR_MOMP predicts responses of TNBC cells to genotoxic agents and the re-sensitization of resistant cells by BCL2 inhibitors. Using absolute protein levels of BAX, BAK, BCL2, BCL(X)L and MCL1 as input for DR_MOMP, we found a strong correlation between model predictions and responses of a panel of TNBC cells to 24 and 48 h cisplatin (R;2; = 0.96 and 0.95, respectively) and paclitaxel treatments (R;2; = 0.94 and 0.95, respectively). This outperformed single protein correlations (best performer BCL(X)L with R;2; of 0.69 and 0.50 for cisplatin and paclitaxel treatments, respectively) and BCL2 proteins ratio (R;2; of 0.
3.BCL-x
Faqar-Uz-Zaman SF;Heinicke U;Meister MT;Vogler M;Fulda S Cancer Lett. 2018 Jan 1;412:131-142. doi: 10.1016/j.canlet.2017.09.025. Epub 2017 Sep 23.
BH3 mimetics are a promising new class of anticancer agents that inhibit antiapoptotic BCL-2 proteins. Here, we report that BH3 mimetics selectively targeting BCL-x;L;, BCL-2 or MCL-1 (i.e. A-1331852, ABT-199, A-1210477) act in concert with multiple chemotherapeutic agents (i.e. vincristine (VCR), etoposide (ETO), doxorubicin, actinomycin D and cyclophosphamide) to induce apoptosis in rhabdomyosarcoma (RMS) cells. Similarly, genetic knockdown of BCL-x;L; primes RMS cells to VCR- or ETO-induced cell death, highlighting the importance of BCL-x;L; in mediating chemotherapy resistance in RMS. A-1331852 and VCR or ETO cooperate to stimulate caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor zVAD.fmk rescues cells from cell death. Molecular studies reveal that VCR/A-1331852 co-treatment causes profound mitotic arrest, which initiates phosphorylation of BCL-2, thereby promoting its inactivation. Also, A-1331852 and VCR or ETO act together to trigger BAX and BAK activation, followed by loss of mitochondrial membrane potential (MMP). Consistently, overexpression of BCL-2 or MCL-1 markedly reduces VCR/A-1331852- or ETO/A-1331852-mediated apoptosis, underscoring that mitochondrial apoptosis represents a key event in synergistic drug interaction.
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