2013
DOI: 10.1038/nm.3048
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Abstract: Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hemat… Show more

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Cited by 2,413 publications
(2,139 citation statements)
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References 46 publications
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“…To further validate this model, we used ABT-199, a first-in-class selective inhibitor of BCL-2. 10 In agreement with previous observations, 10 ABT-199 was selective in inducing apoptosis in the FL5.12 cells overexpressing BCL-2 ( Figure 4a) and was much less potent in the BCL-X L -dependent system (Figure 5a). UCB-1350883 induced a concentration-dependent apoptosis in a BCL-2-dependent system ( Figure 4a); however, at high concentrations it also induced apoptosis in a BCL-X L -dependent system (Figure 5a), suggesting that it shows some selectivity to BCL-2.…”
Section: Resultssupporting
confidence: 92%
See 1 more Smart Citation
“…To further validate this model, we used ABT-199, a first-in-class selective inhibitor of BCL-2. 10 In agreement with previous observations, 10 ABT-199 was selective in inducing apoptosis in the FL5.12 cells overexpressing BCL-2 ( Figure 4a) and was much less potent in the BCL-X L -dependent system (Figure 5a). UCB-1350883 induced a concentration-dependent apoptosis in a BCL-2-dependent system ( Figure 4a); however, at high concentrations it also induced apoptosis in a BCL-X L -dependent system (Figure 5a), suggesting that it shows some selectivity to BCL-2.…”
Section: Resultssupporting
confidence: 92%
“…The design of ABT-199, another related analogue that selectively inhibits BCL-2, but not BCL-X L , seems to circumvent this issue. 10 Thus, a highly specific inhibitor of one BCL-2 family member may be required for the treatment of some tumours. Of the different BCL-2 family members, as the survival of most tumours is not dependent on a single antiapoptotic BCL-2 protein, efficient treatment will more commonly require either a pan-BCL-2 family protein inhibitor or a combination of inhibitors that neutralises both classes of antiapoptotic BCL-2 family proteins.…”
mentioning
confidence: 99%
“…Consistent with this, we previously found imatinib is not senolytic in preadipocytes despite resembling D structurally, targeting many of the same tyrosine kinases, and having similar clinical indications (Modugno, 2014; Zhu et al ., 2015). Additionally, N can cause bleeding by affecting platelets and can cause neutropenia, while newer congeners may have less of these effects (Tse et al ., 2008; Souers et al ., 2013), further emphasizing a need for medicinal chemical optimization. We caution that people should not take N and physicians should not prescribe it for its senolytic effects unless clinical trials show N is effective and safe for these indications.…”
Section: Discussionmentioning
confidence: 99%
“…168,169 This problem can be circumvented in the context of BCL-2-dependent tumours by using ABT-199/venetoclax, a BH3-mimetic that only inhibits BCL-2 and is showing great promise for the treatment of CLL. 170 Moreover, to prevent unacceptable collateral damage to normal tissues, BH3-mimetics may best be used in combination therapies with drugs that only affect cancer cells, such as inhibitors of oncogenic kinases (e.g., Gleevec to inhibit BCR-ABL in CML, Vemurafenib to inhibit mutant BRAF in melanoma), rather than using them with cytotoxic drugs that cause DNA damage in both malignant as well as non-transformed cells. 160 …”
Section: The Role Of the Bcl-2-regulated Apoptotic Pathway In Cancermentioning
confidence: 99%