An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Jennifer R. Molina; Yuting Sun; Marina Protopopova; Sonal Gera; Madhavi Bandi; Christopher Bristow; Timothy McAfoos; Pietro Morlacchi; Jeffrey Ackroyd; Ahmed Noor A. Agip; Gheath Al-Atrash; John Asara; Jennifer Bardenhagen; Caroline C. Carrillo; Christopher Carroll; Edward Chang; Stefan Ciurea; Jason B. Cross; Barbara Czako; Angela Deem; Naval Daver; John Frederick De Groot; Jian Wen Dong; Ningping Feng; Guang Gao; Jason Gay; Mary Geck Do; Jennifer Greer; Virginia Giuliani; Jing Han; Lina Han; Verlene K. Henry; Judy Hirst; Sha Huang; Yongying Jiang; Zhijun Kang; Tin Khor; Sergej Konoplev; Yu Hsi Lin; Gang Liu; Alessia Lodi; Timothy Lofton; Helen Ma; Mikhila Mahendra; Polina Matre; Robert Mullinax; Michael Peoples; Alessia Petrocchi; Jaime Rodriguez-Canale; Riccardo Serreli; Thomas Shi; Melinda Smith; Yoko Tabe; Jay Theroff; Stefano Tiziani; Quanyun Xu; Qi Zhang; Florian Muller; Ronald A. Depinho; Carlo Toniatti; Giulio F. Draetta; Timothy P. Heffernan; Marina Konopleva; Philip Jones; M. Emilia Di Francesco; Joseph R. Marszalek

doi:10.1038/s41591-018-0052-4

An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Jennifer R. Molina, Yuting Sun, Marina Protopopova, Sonal Gera, Madhavi Bandi, Christopher Bristow, Timothy McAfoos, Pietro Morlacchi, Jeffrey Ackroyd, Ahmed Noor A. Agip, Gheath Al-Atrash, John Asara, Jennifer Bardenhagen, Caroline C. Carrillo, Christopher Carroll, Edward Chang, Stefan Ciurea, Jason B. Cross, Barbara Czako, Angela DeemNaval Daver, John Frederick De Groot, Jian Wen Dong, Ningping Feng, Guang Gao, Jason Gay, Mary Geck Do, Jennifer Greer, Virginia Giuliani, Jing Han, Lina Han, Verlene K. Henry, Judy Hirst, Sha Huang, Yongying Jiang, Zhijun Kang, Tin Khor, Sergej Konoplev, Yu Hsi Lin, Gang Liu, Alessia Lodi, Timothy Lofton, Helen Ma, Mikhila Mahendra, Polina Matre, Robert Mullinax, Michael Peoples, Alessia Petrocchi, Jaime Rodriguez-Canale, Riccardo Serreli, Thomas Shi, Melinda Smith, Yoko Tabe, Jay Theroff, Stefano Tiziani, Quanyun Xu, Qi Zhang, Florian Muller, Ronald A. Depinho, Carlo Toniatti, Giulio F. Draetta, Timothy P. Heffernan, Marina Konopleva, Philip Jones, M. Emilia Di Francesco, Joseph R. Marszalek

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Abstract

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

Original language	English (US)
Pages (from-to)	1036-1046
Number of pages	11
Journal	Nature medicine
Volume	24
Issue number	7
DOIs	https://doi.org/10.1038/s41591-018-0052-4
State	Published - Jul 1 2018

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Molina, J. R., Sun, Y., Protopopova, M., Gera, S., Bandi, M., Bristow, C., McAfoos, T., Morlacchi, P., Ackroyd, J., Agip, A. N. A., Al-Atrash, G., Asara, J., Bardenhagen, J., Carrillo, C. C., Carroll, C., Chang, E., Ciurea, S., Cross, J. B., Czako, B., ... Marszalek, J. R. (2018). An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nature medicine, 24(7), 1036-1046. https://doi.org/10.1038/s41591-018-0052-4

Molina, JR, Sun, Y, Protopopova, M, Gera, S, Bandi, M, Bristow, C, McAfoos, T, Morlacchi, P, Ackroyd, J, Agip, ANA, Al-Atrash, G, Asara, J, Bardenhagen, J, Carrillo, CC, Carroll, C, Chang, E, Ciurea, S, Cross, JB, Czako, B, Deem, A, Daver, N, De Groot, JF, Dong, JW, Feng, N, Gao, G, Gay, J, Do, MG, Greer, J, Giuliani, V , Han, J, Han, L, Henry, VK, Hirst, J, Huang, S, Jiang, Y, Kang, Z, Khor, T, Konoplev, S, Lin, YH, Liu, G, Lodi, A, Lofton, T, Ma, H, Mahendra, M, Matre, P, Mullinax, R, Peoples, M, Petrocchi, A, Rodriguez-Canale, J, Serreli, R, Shi, T, Smith, M, Tabe, Y, Theroff, J, Tiziani, S, Xu, Q , Zhang, Q, Muller, F, Depinho, RA, Toniatti, C, Draetta, GF, Heffernan, TP, Konopleva, M, Jones, P, Di Francesco, ME & Marszalek, JR 2018, 'An inhibitor of oxidative phosphorylation exploits cancer vulnerability', Nature medicine, vol. 24, no. 7, pp. 1036-1046. https://doi.org/10.1038/s41591-018-0052-4

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title = "An inhibitor of oxidative phosphorylation exploits cancer vulnerability",

abstract = "Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.",

author = "Molina, {Jennifer R.} and Yuting Sun and Marina Protopopova and Sonal Gera and Madhavi Bandi and Christopher Bristow and Timothy McAfoos and Pietro Morlacchi and Jeffrey Ackroyd and Agip, {Ahmed Noor A.} and Gheath Al-Atrash and John Asara and Jennifer Bardenhagen and Carrillo, {Caroline C.} and Christopher Carroll and Edward Chang and Stefan Ciurea and Cross, {Jason B.} and Barbara Czako and Angela Deem and Naval Daver and {De Groot}, {John Frederick} and Dong, {Jian Wen} and Ningping Feng and Guang Gao and Jason Gay and Do, {Mary Geck} and Jennifer Greer and Virginia Giuliani and Jing Han and Lina Han and Henry, {Verlene K.} and Judy Hirst and Sha Huang and Yongying Jiang and Zhijun Kang and Tin Khor and Sergej Konoplev and Lin, {Yu Hsi} and Gang Liu and Alessia Lodi and Timothy Lofton and Helen Ma and Mikhila Mahendra and Polina Matre and Robert Mullinax and Michael Peoples and Alessia Petrocchi and Jaime Rodriguez-Canale and Riccardo Serreli and Thomas Shi and Melinda Smith and Yoko Tabe and Jay Theroff and Stefano Tiziani and Quanyun Xu and Qi Zhang and Florian Muller and Depinho, {Ronald A.} and Carlo Toniatti and Draetta, {Giulio F.} and Heffernan, {Timothy P.} and Marina Konopleva and Philip Jones and {Di Francesco}, {M. Emilia} and Marszalek, {Joseph R.}",

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doi = "10.1038/s41591-018-0052-4",

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AU - Molina, Jennifer R.

AU - Sun, Yuting

AU - Protopopova, Marina

AU - Gera, Sonal

AU - Bandi, Madhavi

AU - Bristow, Christopher

AU - McAfoos, Timothy

AU - Morlacchi, Pietro

AU - Ackroyd, Jeffrey

AU - Agip, Ahmed Noor A.

AU - Al-Atrash, Gheath

AU - Asara, John

AU - Bardenhagen, Jennifer

AU - Carrillo, Caroline C.

AU - Carroll, Christopher

AU - Chang, Edward

AU - Ciurea, Stefan

AU - Cross, Jason B.

AU - Czako, Barbara

AU - Deem, Angela

AU - Daver, Naval

AU - De Groot, John Frederick

AU - Dong, Jian Wen

AU - Feng, Ningping

AU - Gao, Guang

AU - Gay, Jason

AU - Do, Mary Geck

AU - Greer, Jennifer

AU - Giuliani, Virginia

AU - Han, Jing

AU - Han, Lina

AU - Henry, Verlene K.

AU - Hirst, Judy

AU - Huang, Sha

AU - Jiang, Yongying

AU - Kang, Zhijun

AU - Khor, Tin

AU - Konoplev, Sergej

AU - Lin, Yu Hsi

AU - Liu, Gang

AU - Lodi, Alessia

AU - Lofton, Timothy

AU - Ma, Helen

AU - Mahendra, Mikhila

AU - Matre, Polina

AU - Mullinax, Robert

AU - Peoples, Michael

AU - Petrocchi, Alessia

AU - Rodriguez-Canale, Jaime

AU - Serreli, Riccardo

AU - Shi, Thomas

AU - Smith, Melinda

AU - Tabe, Yoko

AU - Theroff, Jay

AU - Tiziani, Stefano

AU - Xu, Quanyun

AU - Zhang, Qi

AU - Muller, Florian

AU - Depinho, Ronald A.

AU - Toniatti, Carlo

AU - Draetta, Giulio F.

AU - Heffernan, Timothy P.

AU - Konopleva, Marina

AU - Jones, Philip

AU - Di Francesco, M. Emilia

AU - Marszalek, Joseph R.

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N2 - Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

AB - Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

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An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Abstract

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MD Anderson CCSG core facilities

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