The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts
Noortje van Gils1, Tania Martiañez Canales1, Eline Vermue1
1Department of Hematology, Amsterdam UMC Location VUmc, Cancer Center Amsterdam, the Netherlands.
Abstract:
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.
Insights
Novel dual inhibitors NEO1132 and NEO2734 target BET and CBP/p300 proteins to treat acute myeloid leukemia (AML). These drugs reduce AML cell viability, eliminate leukemic stem cells, and show promise for clinical translation.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Acute myeloid leukemia (AML) is driven by transcriptional dysregulation, leading to blocked differentiation and uncontrolled self-renewal.
- Current epigenetic therapies targeting bromodomain and extraterminal domain (BET) proteins and CBP/p300 show limited efficacy due to resistance and failure to eradicate leukemic stem cells.
Purpose of the Study:
- To evaluate the efficacy of two novel oral inhibitors, NEO1132 and NEO2734, targeting both BET and CBP/p300 proteins in primary AML.
- To assess the potential of dual BET and CBP/p300 inhibition as a therapeutic strategy for AML.
Main Methods:
- Testing NEO1132 and NEO2734 on AML cell lines and primary AML cells.
- Assessing the drugs' ability to induce apoptosis and eliminate leukemic stem/progenitor cells.
- Evaluating NEO2734's efficacy in combination chemotherapy using an in vivo AML patient-derived mouse model.
Main Results:
- NEO1132 and NEO2734 effectively reduced the viability of AML cell lines and primary AML cells through apoptosis induction.
- Both NEO drugs demonstrated the ability to eliminate leukemic stem/progenitor cells from patient samples.
- NEO2734 enhanced the effectiveness of combination chemotherapy in an in vivo AML model.
Conclusions:
- Dual inhibition of BET and CBP/p300 proteins with novel agents like NEO2734 represents a promising therapeutic strategy for AML.
- NEO2734 shows potential for clinical translation in treating acute myeloid leukemia patients, particularly in combination therapies.
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