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

András Kotschy, Zoltán Szlavik, James Murray, James Davidson, Ana Leticia Maragno, Gaëtane Le Toumelin-Braizat, Maïa Chanrion, Gemma L. Kelly, Jia Nan Gong, Donia M. Moujalled, Alain Bruno, Márton Csekei, Attila Paczal, Zoltán B. Szabo, Szabolcs Sipos, Gábor Radics, Agnes Proszenyak, Balázs Balint, Levente Ondi, Gábor Blasko & 2 others Giovanna Pomilio, Andrew H. Wei

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

Original languageEnglish
Pages (from-to)477-482
Number of pages6
JournalNature
Volume538
Issue number7626
DOIs
Publication statusPublished - 2016

Cite this

Kotschy, A., Szlavik, Z., Murray, J., Davidson, J., Maragno, A. L., Le Toumelin-Braizat, G., ... Wei, A. H. (2016). The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature, 538(7626), 477-482. https://doi.org/10.1038/nature19830
Kotschy, András ; Szlavik, Zoltán ; Murray, James ; Davidson, James ; Maragno, Ana Leticia ; Le Toumelin-Braizat, Gaëtane ; Chanrion, Maïa ; Kelly, Gemma L. ; Gong, Jia Nan ; Moujalled, Donia M. ; Bruno, Alain ; Csekei, Márton ; Paczal, Attila ; Szabo, Zoltán B. ; Sipos, Szabolcs ; Radics, Gábor ; Proszenyak, Agnes ; Balint, Balázs ; Ondi, Levente ; Blasko, Gábor ; Pomilio, Giovanna ; Wei, Andrew H. / The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. In: Nature. 2016 ; Vol. 538, No. 7626. pp. 477-482.
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title = "The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models",
abstract = "Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.",
author = "Andr{\'a}s Kotschy and Zolt{\'a}n Szlavik and James Murray and James Davidson and Maragno, {Ana Leticia} and {Le Toumelin-Braizat}, Ga{\"e}tane and Ma{\"i}a Chanrion and Kelly, {Gemma L.} and Gong, {Jia Nan} and Moujalled, {Donia M.} and Alain Bruno and M{\'a}rton Csekei and Attila Paczal and Szabo, {Zolt{\'a}n B.} and Szabolcs Sipos and G{\'a}bor Radics and Agnes Proszenyak and Bal{\'a}zs Balint and Levente Ondi and G{\'a}bor Blasko and Giovanna Pomilio and Wei, {Andrew H.}",
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Kotschy, A, Szlavik, Z, Murray, J, Davidson, J, Maragno, AL, Le Toumelin-Braizat, G, Chanrion, M, Kelly, GL, Gong, JN, Moujalled, DM, Bruno, A, Csekei, M, Paczal, A, Szabo, ZB, Sipos, S, Radics, G, Proszenyak, A, Balint, B, Ondi, L, Blasko, G, Pomilio, G & Wei, AH 2016, 'The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models', Nature, vol. 538, no. 7626, pp. 477-482. https://doi.org/10.1038/nature19830

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. / Kotschy, András; Szlavik, Zoltán; Murray, James; Davidson, James; Maragno, Ana Leticia; Le Toumelin-Braizat, Gaëtane; Chanrion, Maïa; Kelly, Gemma L.; Gong, Jia Nan; Moujalled, Donia M.; Bruno, Alain; Csekei, Márton; Paczal, Attila; Szabo, Zoltán B.; Sipos, Szabolcs; Radics, Gábor; Proszenyak, Agnes; Balint, Balázs; Ondi, Levente; Blasko, Gábor; Pomilio, Giovanna; Wei, Andrew H.

In: Nature, Vol. 538, No. 7626, 2016, p. 477-482.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

AU - Kotschy, András

AU - Szlavik, Zoltán

AU - Murray, James

AU - Davidson, James

AU - Maragno, Ana Leticia

AU - Le Toumelin-Braizat, Gaëtane

AU - Chanrion, Maïa

AU - Kelly, Gemma L.

AU - Gong, Jia Nan

AU - Moujalled, Donia M.

AU - Bruno, Alain

AU - Csekei, Márton

AU - Paczal, Attila

AU - Szabo, Zoltán B.

AU - Sipos, Szabolcs

AU - Radics, Gábor

AU - Proszenyak, Agnes

AU - Balint, Balázs

AU - Ondi, Levente

AU - Blasko, Gábor

AU - Pomilio, Giovanna

AU - Wei, Andrew H.

PY - 2016

Y1 - 2016

N2 - Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

AB - Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

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VL - 538

SP - 477

EP - 482

JO - Nature

JF - Nature

SN - 0028-0836

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Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538(7626):477-482. https://doi.org/10.1038/nature19830