bims-midomi 2026-04-19 papers

Leukemia. 2026 Apr 15.

Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models.

Malathi Kandarpa, Luke F Peterson, Harish Potu, Megha Ramappan, Yihong Liu, Avery Polk, Shaomeng Wang, Moshe Talpaz.

MDM2 is an E3 ubiquitin ligase that promotes p53 tumor suppressor degradation and has emerged as a therapeutic target in the treatment of wild-type (wt) TP53 tumors. In acute myeloid leukemia (AML), TP53 mutations are infrequent (15-20%), but wt-p53 is often inactivated through overexpression of MDM2. Thus, MDM2 inhibitors are currently in clinical trials for AML. However, p53 stabilization with inhibitors upregulates MDM2, which limits their clinical efficacy. Proteolysis-targeting chimeric (PROTAC) molecules that degrade MDM2 may overcome this feedback. MD-265 is a PROTAC that recruits CRBN, degrades MDM2, restores p53 and induces apoptosis. We tested MD-265 in ex vivo cultures of 105 primary leukemic stem cells (LSCs). The median cytotoxic IC50 for MD-265 was 16 nM, median IC50 for MI-1061 was 150-fold higher. LSCs with IC50 > 1 µM were classified as MD-265 resistant and harbored mutations in TP53. Normal hematopoietic stem cells showed 100-fold higher IC50 (818 nM) than LSCs. AML patient-derived xenograft (PDX) models in NSG-SGM3 mice were treated with MD-265 or an oral MDM2 inhibitor. In PDX models, MD-265 was not toxic and prolonged survival. MD-265 is a potent and specific MDM2 degrader with broad pre-clinical activity and a promising drug candidate for the treatment of leukemias.

DOI: https://doi.org/10.1038/s41375-026-02957-8

Cancers (Basel). 2026 Mar 25. pii: 1059. [Epub ahead of print]18(7):

MDM4 at the Crossroads: Beyond p53 and MDM2.

Dipesh Thapa, Allison St John, Alejandro Parrales, Atul Ranjan, Tomoo Iwakuma.

MDM4 (Murine Double Minute 4), also known as MDMX, is a crucial negative regulator of the tumor suppressor p53. MDM4 heterodimerizes with MDM2 to enhance MDM2-mediated ubiquitination and degradation of p53, thereby promoting tumorigenesis. Beyond its canonical role in inhibiting p53 activity, recent studies have revealed diverse p53-independent functions. MDM4 interacts with various proteins, including p73, E2F1, casein kinase 1α, PPARα, and TRIM21 to regulate cell cycle progression, β-catenin-mediated pre-leukemic progression, and ferroptosis independent of p53. In addition, MDM4 functions independently of both p53 and MDM2 by interacting with proteins, such as SMAD family members 3/4, retinoblastoma protein (pRB), p21, Nbs1 (also known as Nibrin), mTOR complex 1 (mTORC1), and the Polycomb Repressive Complexes (PRCs) complex, to control cell proliferation and survival, as well as protein degradation, double-strand break (DSB) repair, and replication fork progression. Intriguingly, multiple studies suggest that MDM4 exhibits oncogenic activity independent of p53; however, other reports highlight a potential tumor-suppressive role for MDM4 in the absence of p53. Thus, MDM4's functions extend well beyond the canonical p53-MDM2 axis. A deeper understanding of MDM4 biology may facilitate the development of novel targeted therapies for various cancers.

Keywords: MDM2; MDM4; ferroptosis; independent; p53; replication fork progression; tumorigenesis

DOI: https://doi.org/10.3390/cancers18071059

Cell Death Discov. 2026 Apr 11.

High-throughput strategy for targeting MDM2 in uveal melanoma to reverse radiation therapy resistance.

Qi Zhu, Xi Gong, Sirong Zhang, Jiaqi Zhang, Hongtao Yan.

Uveal melanoma (UM) presents a formidable clinical challenge due to its marked resistance to radiotherapy. In this study, an integrative strategy combining machine learning models with high-throughput screening platforms was employed to identify novel small-molecule inhibitors targeting MDM2, with the aim of overcoming this intrinsic resistance. Transcriptome sequencing and machine learning analysis identified MDM2 as a critical gene associated with UM radiotherapy resistance. Integration of single-cell RNA sequencing data revealed key cells contributing to this resistance. In vitro experiments demonstrated that the MDM2 inhibitor SAR405838 effectively increased radiosensitivity in resistant UM cells by modulating p53 activation, suppressing cell migration and invasion, and inducing DNA damage and apoptosis. This novel approach offers a promising therapeutic strategy for combating UM resistance to radiation therapy.

DOI: https://doi.org/10.1038/s41420-026-02970-x

NPJ Precis Oncol. 2026 Apr 16.

Mitochondrial translocation of MDM2 and TFAM reprograms metabolism in treatment-refractory cancers.

Jie Qing Eu, Nur Afiqah Binte Mohamed Salleh, Jayshree Hirpara, Naoto Ohi, Emiri Omori Takaki, Tuan Zea Tan, Ju Ee Seet, Susan Swee-Shan Hue, Shu Jun Chan, Dorothy Xi Yue Lim, Lingzhi Wang, Regina Tong Xin Wong, Azhar Ali, Yaw Chyn Lim, Boon-Cher Goh, Li Ren Kong, Shazib Pervaiz, Andrea LA Wong.

Tyrosine kinase inhibitors (TKI) are frontline therapies for oncogene-addicted cancers, yet metabolic rewiring frequently drives acquired resistance. Here, we identify a mitochondrial trafficking mechanism that regulates oxidative phosphorylation (OXPHOS) dependence in TKI-resistant tumours. Using resistant cell models and patient-derived materials, we demonstrate that OXPHOS activation is regulated by an AKT-driven, competitive interaction between mitochondrial MDM2 and the mitochondrial transcription factor TFAM at mitochondrial DNA (mtDNA). Mechanistically, adaptive AKT activation promotes cytosolic redistribution of MDM2 with reciprocal accumulation of TFAM in mitochondrial, enhancing mtDNA transcription and OXPHOS activity. To validate this mitochondrial-cytosolic exchange, we develop a quantitative, high-resolution imaging approach to map MDM2 and TFAM localization. In a TKI-resistant clinical cohort (n = 76), we revealed a positive correlation between AKT activation, MDM2 phosphorylation and TFAM mitochondrial trafficking, defining a spatial, subcellular biomarker signature of metabolically reprogrammed TKI resistance. Pharmacologic disruption of the AKT-MDM2-TFAM signaling axis reverse TKI resistance, linking mitochondrial genome regulation to therapy resistance and suggesting a metabolic vulnerability for combinatorial targeting.

DOI: https://doi.org/10.1038/s41698-025-01257-1