Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials

Zhu, Hongyi; Gao, Hui; Ji, Yingying; Zhou, Qin; Du, Zhiqiang; Lin, Tao; Jin, Ying; Yao, Kun; Zhou, Zhenhe

doi:10.1186/s13045-022-01314-3

Cited by 92 publications

(95 citation statements)

References 131 publications

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“…Interestingly, ALRN-6924 does not induce deep levels of apoptosis in healthy tissues, even at the highest doses tested; however, it can induce reversible cell cycle arrest in properly proliferating cells. This concept, called cyclotherapy, offers the chance to selectively protect tissues, such as bone marrow, from cytotoxic chemotherapeutics, thus enabling cancer treatment with fewer side effects [ 128 , 132 ].…”

Section: In the Grip Of Apoptosis—the Desired Future After Venetoclaxmentioning

confidence: 99%

Targeting Apoptosis in AML: Where Do We Stand?

Krawiec

Strzałka²,

Czemerska³

et al. 2022

Cancers

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More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against the emergence of cancer cells. Apoptosis is regulated in part by the BCL-2 family of pro- and anti-apoptotic proteins, whose balance can significantly determine cell survival. Apoptosis evasion plays a key role in tumorigenesis and drug resistance, and thus in the development and progression of AML. Research on the structural and biochemical aspects of apoptosis proteins and their regulators offers promise for new classes of targeted therapies and strategies for therapeutic intervention. This review provides a comprehensive overview of current AML treatment options related to the mechanism of apoptosis, particularly its mitochondrial pathway, and other promising concepts such as neddylation. It pays particular attention to clinically-relevant aspects of current and future AML treatment approaches, highlighting the molecular basis of individual therapies.

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Section: In the Grip Of Apoptosis—the Desired Future After Venetoclaxmentioning

confidence: 99%

Targeting Apoptosis in AML: Where Do We Stand?

Krawiec

Strzałka²,

Czemerska³

et al. 2022

Cancers

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“…Targeting the p53/MDM2 interaction is correspondingly enticing, and investment in the development of such therapeutics has translated into 9 inhibitors currently under investigation in clinical trials. These inhibitors generally target the deep hydrophobic cavity where 3 p53 amino acid residues, Phe19, Trp23, and Leu26, interact with MDM2 78 …”

Section: Targeting Protein-protein Interactionsmentioning

confidence: 99%

“…Although inhibiting MDM2 is a viable therapeutic strategy for cancers with wild-type p53, the remaining 50% of cancers are hindered by p53 mutations; this illustrates a prominent limitation of this approach 78 . Moreover, MDMX, a homolog of MDM2, has been shown to stabilize MDM2, and formations of MDM2/MDMX dimers augment p53 ubiquitination 76,86–88 .…”

Section: Targeting Protein-protein Interactionsmentioning

confidence: 99%

Transcription Factors and Cancer

2023

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Cancer is defined by the presence of uncontrollable cell growth, whereby improper proliferative signaling has overcome regulation by cellular mechanisms. Transcription factors are uniquely situated at the helm of signaling, merging extracellular stimuli with intracellular responses. Therefore, this class of proteins plays a pivotal role in coordinating the correct gene expression levels for maintaining normal cellular functions. Dysregulation of transcription factor activity unsurprisingly drives tumorigenesis and oncogenic transformation. Although this imparts considerable therapeutic potential to targeting transcription factors, their lack of enzymatic activity renders intervention challenging and has contributed to a sense that transcription factors are “undruggable.” Yet, enduring efforts to elucidate strategies for targeting transcription factors as well as a deeper understanding of their interactions with binding partners have led to advancements that are emerging to counter this narrative. Here, we highlight some of these approaches, focusing primarily on therapeutics that have advanced to the clinic.

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“…However, tumors with inactivating mutations in TP53 are resistant to most MDM2 inhibitors (reviewed in refs. [21][22][23] ). To determine whether this correlation was reflected in our DSP results, we visualized MDM2 inhibitor (idasanutlin and AMG-232) sensitivity (determined as DSS asym quantiles) and the TP53 status of our DSP samples in an unsupervised hierarchical clustering heatmap.…”

Section: Drug Sensitivity Profiling and Tumor Board Presentation (C)mentioning

confidence: 99%

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

et al. 2022

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The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.

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Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials

Cited by 92 publications

References 131 publications

Targeting Apoptosis in AML: Where Do We Stand?

Targeting Apoptosis in AML: Where Do We Stand?

Transcription Factors and Cancer

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

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