The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

Kotschy, András; Szlávik, Zoltán; Murray, James B.; Davidson, James; Maragno, Ana Leticia; Toumelin-Braizat, Gaëtane Le; Chanrion, Maïa; Kelly, Gemma L.; Gong, Jianan; Moujalled, Donia; Bruno, Alain; Csékei, Márton; Paczal, Attila; Szabó, Zoltán; Sipos, Szabolcs; Radics, Gábor; Proszenyák, Ágnes; Balint, Balázs; Ondi, Levente; Blaskó, Gábor; Robertson, Alan; Surgenor, A.E.; Dokurno, P.; Chen, I‐Jen; Matassova, Natalia; Smith, Julia; Pedder, C.; Graham, Christopher; Studény, Aurélie; Lysiak-Auvity, Gaëlle; Girard, Anne-Marie; Gravé, Fabienne; Segal, David; Riffkin, Christopher D.; Pomilio, Giovanna; Galbraith, Laura C.A.; Aubrey, Brandon J.; Brennan, Margs S.; Herold, Marco J.; Chang, Catherine; Guasconi, Ghislaine; Cauquil, Nicolas; Melchiore, Fabien; Guigal-Stéphan, Nolwen; Lockhart, Brian P.; Colland, Frédéric; Hickman, John A.; Roberts, Andrew W.; Huang, David C.S.; Wei, Andrew H.; Strasser, Andreas; Lessène, Guillaume; Geneste, Olivier

doi:10.1038/nature19830

Cited by 887 publications

(974 citation statements)

References 51 publications

Supporting

Mentioning

903

Contrasting

Unclassified

Order By: Relevance

“…BH3 mimetic compounds, akin to the recently FDA approved BCL-2-specific inhibitor Venetoclax (ABT-199), 49 or the newly described MCL-1 inhibitor S63845 soon entering first clinical trials, 50 but inhibiting specifically A1, may be useful for the treatment of certain types of lymphoma, melanoma and stomach cancer, as these cancers were found to express abnormally high levels of A1. 21 In conclusion, our studies reveal that A1 is not a vital prosurvival protein in normal physiology.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

et al. 2017

Self Cite

View full text Add to dashboard Cite

The pro-survival proteins of the BCL-2 family regulate the survival of all cells, and genetic deletion models for these proteins have revealed which specific BCL-2 family member(s) is/are critical for the survival of particular cell types. A1 is a pro-survival BCL-2-like protein that is expressed predominantly in haematopoietic cells, and here we describe the characterisation of a novel mouse strain that lacks all three functional isoforms of A1 (A1-a, A1-b and A1-d). Surprisingly, complete loss of A1 caused only minor defects, with significant, although relatively small, decreases in γδTCR T cells, antigen-experienced conventional as well as regulatory CD4 T cells and conventional dendritic cells (cDCs). When examining these cell types in tissue culture, only cDC survival was significantly impaired by the loss of A1. Therefore, A1 appears to be a surprisingly redundant pro-survival protein in the haematopoietic system and other tissues, suggesting that its targeting in cancer may be readily tolerated. Cell Death and Differentiation (2017) 24, 534-545; doi:10.1038/cdd.2016.156; published online 13 Janaury 2017The pro-survival proteins of the BCL-2 family prevent apoptosis 1 and studies using gene-targeted mice have revealed which cell types rely on which pro-survival protein for their survival. For example, Bcl-2 −/− mice exhibit thymic and splenic atrophy, a loss of fur pigment and die~30 days post birth from polycystic kidney disease, attributable to excess lymphocyte, melanocyte and renal epithelial cell apoptosis, respectively. 2-4 Bcl-X −/− mice die before E14.5 of embryonic development because of aberrant death of erythroid and neuronal cells. 5 The generation of chimaeric or tissue-specific Bcl-X −/− revealed a critical role for BCL-XL in the survival of developing lymphocytes 5 and platelets. 6,7 Mcl-1 −/− embryos die before implantation (E3.5), 8 but conditional Mcl-1 deletion models have demonstrated an essential role for MCL-1 in the survival of haematopoietic stem cells, lymphocytes, neurons and cardiomyocytes. 9-15 Bcl-W −/− mice have impaired spermatogenesis. 16,17 A1 remains the only pro-survival BCL-2 family member for which a knockout mouse strain has not been developed. A1 was first discovered as a GM-CSF-inducible gene with significant sequence similarity to BCL-2 and MCL-1, 18 and its human homologue BFL-1 was later identified in fetal liver. 19 Overexpression of A1 protected an IL-3-dependent cell line from growth factor deprivation-induced apoptosis, thus demonstrating its pro-survival function. 20 In mice, A1 expression is restricted to the haematopoietic compartment. 18 Human BFL-1 expression is more widespread, but also predominantly haematopoietic. 21 A1 can be upregulated by NF-κB signalling, and it has been proposed that A1/BFL-1 is important for the survival of several activated immune cell subsets through stimulation of antigen or cytokine receptors. [22][23][24][25] Studies of A1 in mice are complicated by the presence of multiple isoforms that are the result of gene duplication ev...

show abstract

Section: Discussionmentioning

confidence: 99%

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…28,29 Determining the dependence on a particular antiapoptotic BCL-2 family protein has become critical for deciding a personalized therapy. The advent of "BH3 profiling" using specific peptides has led the way, 30,31 although more recent availability of specific small-molecule inhibitors of BCL-xL (Wehi-539, A-1155463, A-1331852) 32,33 and MCL-1 (A-1210477, S63845), 34,35 in addition to inhibition of BCL-2 by venetoclax, has facilitated, at least in an ex vivo culture, a rapid determination of the BCL-2 family protein dependence. These tools make it possible to choose the most effective therapeutics to be used based on a functional output, their ability to induce tumor cell death.…”

Section: Development Of Bh3 Mimetic Drugsmentioning

confidence: 99%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

DDDT

View full text Add to dashboard Cite

B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.

show abstract

“…Because of the key role of MCL1 in protecting malignant cells against anticancer treatments, combinatorial therapy with BH3-binding molecules such as navitoclax may enhance the therapeutic effects of radiotherapy and other treatments. Multiple approaches have been undertaken to directly target MCL1, and several MCL1-specific BH3 mimetics have been identified 39,47 . For example, S63845 binds with high affinity to human MCL1 without appreciable binding to BCL-2 or BCL-X L 47 .…”

Section: The Role Of Mcl1 and Its Targeted Therapy In Lung Cancermentioning

confidence: 99%

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

Tanaka¹

2017

J Cancer Treat & Diagnosis

View full text Add to dashboard Cite

Evasion of apoptosis is one of the typical hallmarks of cancer and a major mechanism for cancer development, tumor growth, and acquisition of resistance to chemotherapy. The anti-apoptotic Bcl-2 protein family, particularly MCL1 and BCL-XL, play an important role in acquisition of apoptosis evasion. MCL1 is a highly unstable protein that is constantly degraded by the ubiquitinproteasome system. An increase in MCL1 protein has been reported in many cancers, including lung cancer, through high mRNA expression or impairment of its degradation systems. To date, much evidence has shown that MCL1 is important for cancer cell survival and drug resistance in lung cancers. In this review, we discuss the role and mechanism of high MCL1 expression in lung cancer.

show abstract

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

Cited by 887 publications

References 51 publications

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

Development of venetoclax for therapy of lymphoid malignancies

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

Contact Info

Product

Resources

About