Targeting both BET and CBP/EP300 proteins with the novel dual inhibitors NEO2734 and NEO1132 leads to anti‐tumor activity in multiple myeloma

Ryan, Katie R.; Giles, Francis J.; Morgan, Gareth J.

doi:10.1111/ejh.13525

Cited by 22 publications

(17 citation statements)

References 46 publications

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“…Inhibitors like NEO2734 and NEO1132 targeting both BET and CBP/p300 proteins could induce the depletion of Myc and inhibition of multiple myeloma growth ( Spriano et al, 2020 ). Sensitivity to the dual inhibitors was only in connection with Myc protein expression levels ( Ryan et al, 2021 ).…”

Section: Inhibitor Progression Of Protein-protein Interaction With Mycmentioning

confidence: 99%

Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

et al. 2021

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MYC, as a well-known oncogene, plays essential roles in promoting tumor occurrence, development, invasion and metastasis in many kinds of solid tumors and hematologic neoplasms. In tumors, the low expression and the short half-life of Myc are reversed, cause tumorigenesis. And proteins that directly interact with different Myc domains have exerted a significant impact in the process of Myc-driven carcinogenesis. Apart from affecting the transcription of Myc target genes, Myc interaction proteins also regulate the stability of Myc through acetylation, methylation, phosphorylation and other post-translational modifications, as well as competitive combination with Myc. In this review, we summarize a series of Myc interacting proteins and recent advances in the related inhibitors, hoping that can provide new opportunities for Myc-driven cancer treatment.

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Section: Inhibitor Progression Of Protein-protein Interaction With Mycmentioning

confidence: 99%

Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

et al. 2021

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“…Inhibition of both BET and CBP/p300 demonstrated to induce a G1-phase cell cycle arrest, 43 , 44 which, in case of CBP/p300 inhibition in multiple myeloma cell lines, also induced downregulation of c-Myc. 44 Similarly, NEO2734 and NEO1132 were recently identified to induce a G1-phase cell cycle arrest in NUT midline carcinoma cells and multiple myeloma cells, 31 , 45 and we therefore investigated the effect of the NEO drugs on cell cycle progression of AML cells. Indeed, after 24 or 48 hours of treatment, NEO2734 could induce a significant G1-phase cell cycle arrest in all 4 tested AML cell lines (Figure 2 A, Supplemental Digital Content, Figure 2A, http://links.lww.com/HS/A176 ).…”

Section: Resultsmentioning

confidence: 99%

The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells

et al. 2021

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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.

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“…Through unbiased signaling pathway inhibitor survey, we demonstrate that ENZ-R cells are hyper-sensitive to the dual inhibitors of BET and CBP/p300 proteins such as NEO2734 [50][51][52] . In agreement with these results, we show that chromatin occupancy of CXXC5 and H3K27ac levels are positively correlated at noncanonical AR target loci and that the BET-CBP/p300 dual inhibitor treatment inhibits CXXC5 protein expression and decreases BRD4 and p300 binding and H3K27ac levels at these loci.…”

Section: Discussionmentioning

confidence: 98%

A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

Wei

et al. 2021

Nat Commun

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Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.

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Targeting both BET and CBP/EP300 proteins with the novel dual inhibitors NEO2734 and NEO1132 leads to anti‐tumor activity in multiple myeloma

Cited by 22 publications

References 46 publications

Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells

A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

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