Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

Shaneice R. Mitchell; Karilyn Larkin; Nicole R. Grieselhuber; Tzung Huei Lai; Matthew Cannon; Shelley Orwick; Pratibha Sharma; Yerdanose Asemelash; Pu Zhang; Virginia M. Goettl; Larry Beaver; Alice Mims; Vinay K. Puduvalli; James S. Blachly; Amy Lehman; Bonnie Harrington; Sally Henderson; Justin T. Breitbach; Katie E. Williams; Shuai Dong; Erkan Baloglu; William Senapedis; Karl Kirschner; Deepa Sampath; Rosa Lapalombella; John C. Byrd

doi:10.1182/bloodadvances.2018024182

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

Shaneice R. Mitchell, Karilyn Larkin, Nicole R. Grieselhuber, Tzung Huei Lai, Matthew Cannon, Shelley Orwick, Pratibha Sharma, Yerdanose Asemelash, Pu Zhang, Virginia M. Goettl, Larry Beaver, Alice Mims, Vinay K. Puduvalli, James S. Blachly, Amy Lehman, Bonnie Harrington, Sally Henderson, Justin T. Breitbach, Katie E. Williams, Shuai DongErkan Baloglu, William Senapedis, Karl Kirschner, Deepa Sampath, Rosa Lapalombella, John C. Byrd

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD¹ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD¹, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

Original language	English (US)
Pages (from-to)	242-255
Number of pages	14
Journal	Blood Advances
Volume	3
Issue number	3
DOIs	https://doi.org/10.1182/bloodadvances.2018024182
State	Published - Feb 12 2019
Externally published	Yes

ASJC Scopus subject areas

Hematology

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Mitchell, S. R., Larkin, K., Grieselhuber, N. R., Lai, T. H., Cannon, M., Orwick, S., Sharma, P., Asemelash, Y., Zhang, P., Goettl, V. M., Beaver, L., Mims, A., Puduvalli, V. K., Blachly, J. S., Lehman, A., Harrington, B., Henderson, S., Breitbach, J. T., Williams, K. E., ... Byrd, J. C. (2019). Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia. Blood Advances, 3(3), 242-255. https://doi.org/10.1182/bloodadvances.2018024182

Mitchell, SR, Larkin, K, Grieselhuber, NR, Lai, TH, Cannon, M, Orwick, S, Sharma, P, Asemelash, Y, Zhang, P, Goettl, VM, Beaver, L, Mims, A, Puduvalli, VK, Blachly, JS, Lehman, A, Harrington, B, Henderson, S, Breitbach, JT, Williams, KE, Dong, S, Baloglu, E, Senapedis, W, Kirschner, K, Sampath, D, Lapalombella, R & Byrd, JC 2019, 'Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia', Blood Advances, vol. 3, no. 3, pp. 242-255. https://doi.org/10.1182/bloodadvances.2018024182

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title = "Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia",

abstract = "Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD1 and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD1, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.",

author = "Mitchell, {Shaneice R.} and Karilyn Larkin and Grieselhuber, {Nicole R.} and Lai, {Tzung Huei} and Matthew Cannon and Shelley Orwick and Pratibha Sharma and Yerdanose Asemelash and Pu Zhang and Goettl, {Virginia M.} and Larry Beaver and Alice Mims and Puduvalli, {Vinay K.} and Blachly, {James S.} and Amy Lehman and Bonnie Harrington and Sally Henderson and Breitbach, {Justin T.} and Williams, {Katie E.} and Shuai Dong and Erkan Baloglu and William Senapedis and Karl Kirschner and Deepa Sampath and Rosa Lapalombella and Byrd, {John C.}",

note = "Publisher Copyright: {\textcopyright} 2019 by The American Society of Hematology.",

year = "2019",

month = feb,

day = "12",

doi = "10.1182/bloodadvances.2018024182",

language = "English (US)",

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T1 - Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

AU - Mitchell, Shaneice R.

AU - Larkin, Karilyn

AU - Grieselhuber, Nicole R.

AU - Lai, Tzung Huei

AU - Cannon, Matthew

AU - Orwick, Shelley

AU - Sharma, Pratibha

AU - Asemelash, Yerdanose

AU - Zhang, Pu

AU - Goettl, Virginia M.

AU - Beaver, Larry

AU - Mims, Alice

AU - Puduvalli, Vinay K.

AU - Blachly, James S.

AU - Lehman, Amy

AU - Harrington, Bonnie

AU - Henderson, Sally

AU - Breitbach, Justin T.

AU - Williams, Katie E.

AU - Dong, Shuai

AU - Baloglu, Erkan

AU - Senapedis, William

AU - Kirschner, Karl

AU - Sampath, Deepa

AU - Lapalombella, Rosa

AU - Byrd, John C.

PY - 2019/2/12

Y1 - 2019/2/12

N2 - Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD1 and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD1, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

AB - Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD1 and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD1, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

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EP - 255

JO - Blood Advances

JF - Blood Advances

IS - 3

ER -

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

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