Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer

Adams, Clare M.; Mitra, Ramkrishna; Xiao, You‐Cai; Michener, Peter; Palazzo, Juan; Chao, Allen; Gour, Jitendra; Cassel, Joel; Salvino, Joseph M.; Eischen, Christine M.

doi:10.1158/2159-8290.cd-22-1131

Cited by 49 publications

(23 citation statements)

References 90 publications

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“…This newly developed compound, AC-03-087 (JG-03-111) (Figure 3I), showed potent PARP1 binding affinity in the HTRF competitive displacement assay against the fluorescent probe, JG-03-142, with low nanomolar affinity of AC-03-087 for PARP1 (IC50 = 3.07 ± 0.881 nM) compared to Olaparib (IC50 = 1.42 ± 0.335 nM) (Figure S3C). We also evaluated AC-03-087 for its ability to form a ternary complex using the AlphaScreen technology 26,27 and confirmed that AC-03-087 treatment induces a stable ternary complex between PARP1 and MDM2 (Figure S3D). In line with these data, dose escalation experiments conducted with AC-03-087 in HeLa cells using an In-Cell Western assay 28 confirmed specific degradation of PARP1 at low nanomolar concentrations (Figure 3J).…”

Section: ■ Resultsmentioning

confidence: 60%

A Tandem-Affinity Purification Method for Identification of Primary Intracellular Drug-Binding Proteins

Islam,

Gour,

Beer

et al. 2024

ACS Chem. Biol.

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In the field of drug discovery, understanding how small molecule drugs interact with cellular components is crucial. Our study introduces a novel methodology to uncover primary drug targets using Tandem Affinity Purification for identification of Drug-Binding Proteins (TAP-DBP). Central to our approach is the generation of a FLAG-hemagglutinin (HA)-tagged chimeric protein featuring the FKBP12(F36V) adaptor protein and the TurboID enzyme. Conjugation of drug molecules with the FKBP12(F36V) ligand allows for the coordinated recruitment of drug-binding partners effectively enabling in-cell TurboID-mediated biotinylation. By employing a tandem affinity purification protocol based on FLAG-immunoprecipitation and streptavidin pulldown, alongside mass spectrometry analysis, TAP-DBP allows for the precise identification of drug-primary binding partners. Overall, this study introduces a systematic, unbiased method for identification of drug−protein interactions, contributing a clear understanding of target engagement and drug selectivity to advance the mode of action of a drug in cells.

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Section: ■ Resultsmentioning

confidence: 60%

A Tandem-Affinity Purification Method for Identification of Primary Intracellular Drug-Binding Proteins

Islam,

Gour,

Beer

et al. 2024

ACS Chem. Biol.

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“…Remarkably, our results are consistent with recent findings that MDM2 p90 depletion leads to cancer cell death regardless of p53 mutation status. [ 28 ]…”

Section: Resultsmentioning

confidence: 99%

“…It is important to note that our findings are consistent with recent studies showing that, in triple‐negative breast cancer, MDM2 p90 elimination by MDM2‐PROTAC resulted in cell death regardless of the p53 mutation status, accompanied by the posttranscriptional stabilization of p73 but not p63. [ 28 ] The upregulation of p73 was confirmed to be a consequence of MDM2 p90 depletion and was crucial for cell death induction, although the exact mechanism remains unknown. It was speculated that MDM2 p90 depletion completely eliminates its p53‐dependent and p53‐independent oncogenic effects, including p73 activation.…”

Section: Discussionmentioning

confidence: 99%

“…Remarkably, our results are consistent with recent findings that MDM2 p90 depletion leads to cancer cell death regardless of p53 mutation status. [28] The efficiency of ACP52C-mediated growth inhibition in mutant p53-bearing cancers could be further modulated by the upregulation and phosphorylation of mutant p53, as well as other cellular contexts resulting from specific p53 mutations. We found that ACP52C-induced growth inhibition occurred regardless of p53 mutation status in general, and GI 50 values in mutant p53-bearing cancers showed only slight deviations among them, which were higher than in p53 wildtype or null cancers (Figure 6B).…”

Section: Acp52c Induces Cancer-specific Apoptosis Via Mdm2 P90 Downre...mentioning

confidence: 99%

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A Cell‐Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer‐Specific Synthetic Lethality

Son,

Kim,

Choi

et al. 2023

Advanced Science

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Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof‐of‐principle evidence is presented that a cell‐penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene‐addicted cancer cells through transcription activity‐independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2‐p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome‐wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C‐resistant cancers. This study enhances the understanding of ACP52C‐induced cancer‐specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

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“…Currently, many compounds that can reactivate p53 or destabilize mutant p53, such as APR‐246 and COTI‐2, have been approved for clinical trials 32 . At the same time, MDM2 inhibitors have also been related to research, and inhibition of MDM2–p53 interaction has become a possible therapy 33–37 . However, the corresponding research has mainly focused on the mutation site of TP53 or p53, and the relevant clinical transformation is still in its infancy 38 .…”

Section: Introductionmentioning

confidence: 99%

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

Shen¹,

Wang²,

Mao³

et al. 2023

MedComm

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Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling‐targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor‐promoting role by blocking the mitochondria‐dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.

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Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer

Cited by 49 publications

References 90 publications

A Tandem-Affinity Purification Method for Identification of Primary Intracellular Drug-Binding Proteins

A Tandem-Affinity Purification Method for Identification of Primary Intracellular Drug-Binding Proteins

A Cell‐Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer‐Specific Synthetic Lethality

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

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