Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis

Nguyen, Mai; Marcellus, Richard; Roulston, Anne; Watson, Mark; Serfass, Lucile; Madiraju, S.R. Murthy; Goulet, Denis; Viallet, Jean; Bélec, Laurent; Billot, Xavier; Acoca, Stéphane; Purisima, Enrico O.; Wiegmans, Adrian P.; Cluse, Leonie A.; Johnstone, Ricky W.; Beauparlant, Pierre; Shore, Gordon C.

doi:10.1073/pnas.0709443104

Cited by 611 publications

(613 citation statements)

References 44 publications

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“…Although MCL-1 is structurally similar to other BCL-2 family members, there are differences in its BH3-binding grove, resulting in a lower affinity of commonly available BCL-2 antagonists. Although obatoclax was reported to be a broad-spectrum BCL-2 family inhibitor that antagonised MCL-1, 15 it did not act as such but rather behaved like a mitochondrial toxin. 4,8,9 In an attempt to design a specific MCL-1 inhibitor, the structural features of BH3I-1, as an inhibitor of BCL-2 proteins, were incorporated into the synthesis of compounds 6 and 7.…”

Section: Discussionmentioning

confidence: 98%

“…Several putative selective inhibitors of MCL-1, including obatoclax (GX-1570), 15 two derivatives of rhodanine (compounds 6 and 7), 16 TW-37, 17 derivatives of apogossypol/ apogossypolone (BI97C1 (commonly referred to as sabutoclax), BI97C10 and BI112D1 (also called BI97D6) [18][19][20] and MCL-1 inhibitor molecule (MIM-1) 21 have been synthesised based on different approaches including modelling studies, in silico and in vitro screens (Figure 1). In this study, we evaluate these compounds either as potentially selective MCL-1 inhibitors or as pan-BCL-2 family inhibitors.…”

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confidence: 99%

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Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-X L but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak-and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2-or BCL-X L -dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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“…In some of the cancer cells Mcl-I conferred resistance to apoptotic cell death induced by either ABT-737 (A small molecule that targets Bcl2) or bortezomib (Proteosome inhibitor). Synergetic use of GX15-070 with either ABT 737 or bortezomib overcomes the apoptotic resistance in cancer cells (Nguyen et al 2007). These experimental findings show that GX15-070 can be used in combination with other drugs and can overcome apoptosis resistance.…”

Section: Potentiation Of Apoptosis In Cancer Therapymentioning

confidence: 99%

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

Chaabane

User

El-Gazzah

et al. 2012

Arch. Immunol. Ther. Exp.

252

149

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“…Further studies are also necessary to understand the mechanism of action of OBX. OBX is a synthetic indolylprodigiosin derivative, which was developed by GeminX Pharmaceuticals (recently acquired by Cephalon) and was described as a BH3 mimetic drug (3).…”

Section: Introductionmentioning

confidence: 99%

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and Obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modelling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.3

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Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis

Abstract: Bcl-2 ͉ melanoma ͉ Bax ͉ Bak ͉ caspase

Cited by 611 publications

References 44 publications

Evaluation and critical assessment of putative MCL-1 inhibitors

Evaluation and critical assessment of putative MCL-1 inhibitors

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

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