The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells
Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML p...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-08-01
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| Series: | HemaSphere |
| Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000610 |
| _version_ | 1797284142067482624 |
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| author | Noortje van Gils Tania Martiañez Canales Eline Vermue Arjo Rutten Fedor Denkers Tiem van der Deure Gert J. Ossenkoppele Francis Giles Linda Smit |
| author_facet | Noortje van Gils Tania Martiañez Canales Eline Vermue Arjo Rutten Fedor Denkers Tiem van der Deure Gert J. Ossenkoppele Francis Giles Linda Smit |
| author_sort | Noortje van Gils |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation. |
| first_indexed | 2024-03-07T17:43:48Z |
| format | Article |
| id | doaj.art-3fb817b7e6284c9b96430bb8fba91701 |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-03-07T17:43:48Z |
| publishDate | 2021-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj.art-3fb817b7e6284c9b96430bb8fba917012024-03-02T15:26:57ZengWileyHemaSphere2572-92412021-08-0158e61010.1097/HS9.0000000000000610202108000-00001The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor CellsNoortje van Gils0Tania Martiañez Canales1Eline Vermue2Arjo Rutten3Fedor Denkers4Tiem van der Deure5Gert J. Ossenkoppele6Francis Giles7Linda Smit81 Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the Netherlands1 Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the Netherlands1 Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the Netherlands1 Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the Netherlands1 Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the Netherlands1 Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the Netherlands1 Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the Netherlands2 Epigene Therapeutics Consortium, Chicago, Illinois, USA1 Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the NetherlandsAcute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation.http://journals.lww.com/10.1097/HS9.0000000000000610 |
| spellingShingle | Noortje van Gils Tania Martiañez Canales Eline Vermue Arjo Rutten Fedor Denkers Tiem van der Deure Gert J. Ossenkoppele Francis Giles Linda Smit The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells HemaSphere |
| title | The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells |
| title_full | The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells |
| title_fullStr | The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells |
| title_full_unstemmed | The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells |
| title_short | The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells |
| title_sort | novel oral bet cbp p300 dual inhibitor neo2734 is highly effective in eradicating acute myeloid leukemia blasts and stem progenitor cells |
| url | http://journals.lww.com/10.1097/HS9.0000000000000610 |
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