BCL-2 family antagonists for cancer therapy

Lessène, Guillaume; Czabotar, P.E.; Colman, Peter M.

doi:10.1038/nrd2658

Cited by 553 publications

(531 citation statements)

References 109 publications

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“…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. 16,25 On the basis of isothermal calorimetry data, compound 7 was reported to bind exclusively to MCL-1, whereas compound 6 although binding more tightly to MCL-1 also bound to BCL-X L .…”

Section: Discussionmentioning

confidence: 99%

“…Most of these inhibitors have been shown to be rather non-specific with the notable exception of ABT-737 and its orally active analogue ABT-263 (navitoclax), the latter of which has recently entered clinical trials for treating various haematological malignancies. [4][5][6][7][8][9] Both ABT-737 and ABT-263 inhibit BCL-2, BCL-X L and BCL-w but not MCL-1 or BCL2A1. 5,6 Some tumours are dependent or addicted to a specific anti-apoptotic protein, such as the dependence of chronic lymphocytic leukaemia (CLL) cells for survival on BCL-2.…”

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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: 99%

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Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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“…12 Initiation of the BCL-2-regulated apoptotic pathway is controlled, as the name implies, by interactions between members of the BCL-2 protein family. [14][15][16][17][18][19] This family consists of three groups of structurally related proteins: the pro-survival BCL-2-like proteins, the multi-BH domain pro-apoptotic BAX/BAK proteins, and the pro-apoptotic BH3-only proteins.…”

Section: The Bcl-2-regulated Apoptotic Pathwaymentioning

confidence: 99%

“…BH3-mimetics bind and inhibit the pro-survival BCL-2 family members and thereby activate apoptosis in cancer cells. 16 ABT-737 and its clinical analogue ABT-263 (navitoclax) exemplify this new therapeutic class, with the latter compound currently in phase 2 clinical trials. 161,162 Both compounds bind to BCL-2, BCL-XL and BCL-W (but not to MCL-1 or A1) displacing the endogenous BH3-only proteins, which can then bind to MCL-1, A1 and some of them also to BAX/BAK.…”

Section: The Role Of the Bcl-2-regulated Apoptotic Pathway In Cancer mentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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“…The BCL-2 antiapoptotic protein contains a BH3 binding groove that accommodates the BH3 domain of proapoptotic proteins, therefore impeding their action and blocking apoptosis. This structural feature provides the platform to develop peptides and chemical compounds that bind to the groove of the antiapoptotic protein, thus reliving the apoptotic block and promoting cell death (Lessene et al, 2008). However, initial phase I and II clinical trials administering the BH3-mimetic gossypol were not encouraging.…”

Section: Current Therapeutic Paradigms To Treat Cancermentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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BCL-2 family antagonists for cancer therapy

Cited by 553 publications

References 109 publications

Evaluation and critical assessment of putative MCL-1 inhibitors

Evaluation and critical assessment of putative MCL-1 inhibitors

The BCL-2 protein family, BH3-mimetics and cancer therapy

Towards novel paradigms for cancer therapy

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