MS1943 / Tisch Cancer Institute, Mount Sinai - LARVOL DELTA

Efficacy of Protac-Based EZH2 Degrader MS1943 in Lymphoid Malignancies: A Comprehensive Study on the Combined Effects of MS1943 and Ibrutinib (ASH 2023) - "The results demonstrated that MS1943 exhibited significantly greater inhibitory effects than Tazemetostat in all lymphoma cell lines tested, particularly in B-cell lymphomas. MS1943 treatment resulted in increased expression of UPR pathway effectors, suggesting a correlation between the observed anti-proliferative effects and the differential expression of these factors. The combination of MS1943 and Ibrutinib demonstrated significant inhibitory effects across all B-cell lymphoma cell lines, with the most prominent cytotoxicity observed after 72 hours of culture."

Clinical • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Targeted Protein Degradation • BBC3 • XBP1

EZH2 contributes to the malignant behavior and its pharmacological degradation effectively inhibits cell growth in grade 3 meningioma (EANO 2025) - "The EZH2 selective degrader MS-1943 exerts more potent effects in two different meningioma cell lines in vitro, then the histone methyltransferase inhibitor EPZ-6438. These findings suggest that non-conventional, histone methylation-independent functions of EZH2 play a fundamental role and maybe more promising targets of potential future therapeutic approaches in these tumors.Support: National Research, Development and Innovation Office grant NKFIH-PD-146549."

Brain Cancer • Meningioma • Oncology • Solid Tumor • CDKN1A • EZH2 • FOXM1 • TP53

EZH2 is a druggable target of resistance to CDK4/6 inhibitors in breast cancer (EORTC-NCI-AACR 2024) - P=N/A | " We established palbociclib- and abemaciclib- resistant (p/a) models using three commercial breast cancer cell lines...To assess EZH2 therapeutic potential in p/a resistant cells, we targeted EZH2 expression with shRNAs and the EZH2 degrader MS1943 as well as inhibited its catalytic activity with tazemetostat... We identified a novel mechanisms of resistance to CDK 4/6 inhibition in MBCs. If validated in ongoing in vivo studies, these preclinical observations may set the foundation for future clinical investigations assessing whether anti-EZH2 compounds in combination with endocrine therapy can prevent, delay, or directly target MBCs resistant to CDK 4/6 inhibition."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • EZH2 • HER-2

Double inhibition of EZH2 and EGFR/HER2: A new strategy for Burkitt lymphoma therapy (ICKSH 2024) - "The treatment also upregulates p53 and Bax expres- sions, highlighting its potential as an effective BL therapy. Conclusion : The study indicates that combining MS1943 and Lapatinib effectively induces apoptosis in Burkitt's lymphoma, showing prom- ising clinical potential with synergistic anti-proliferative and caspase pathway activation effects, warranting further clinical validation."

Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • CASP3 • EGFR • HER-2 • MYC • PARP1

Dual Targeting of EZH2 Degradation and EGFR/HER2 Inhibition for Enhanced Efficacy against Burkitt's Lymphoma. (PubMed, Cancers (Basel)) - "We observed that a combination of MS1943 and lapatinib induced apoptosis in Daudi cells and caused cell cycle arrest at the S and G2/M phases in both Ramos and Daudi cells. This strategy, using a combination of MS1943 and lapatinib, presents a promising therapeutic approach for treating lymphoma and potentially Burkitt's lymphoma."

Journal • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Targeted Protein Degradation • HER-2

Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt's lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib. (PubMed, Front Oncol) - "In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt's lymphoma. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt's lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt's lymphoma."

Journal • Burkitt Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Targeted Protein Degradation • CASP3

Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib (Front Oncol) - "Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt’s lymphoma cells."

Preclinical • Burkitt Lymphoma

Dual Targeting of EZH2 Degradation and EGFR/HER2 Inhibition for Enhanced Efficacy against Burkitt’s Lymphoma (Multidisciplinary Digital Publishing Institute) - "We conducted a study using a combination of MS1943, EZH2 degrader, lapatinib, and HER2/neu-EGFR inhibitor. We demonstrated that a combination of MS1943 and lapatinib induced apoptosis in Daudi cells with S and G2/M phase arrest in Ramos and Daudi cells. These promising agents could prove to be a new therapeutic option against BL."

Preclinical • Burkitt Lymphoma

Overcoming the Therapeutic Limitations of EZH2 Inhibitors in Burkitt's Lymphoma: A Comprehensive Study on the Combined Effects of MS1943 and Ibrutinib (Front Oncol) - "Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt's lymphoma cells."

Preclinical • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma. (PubMed, Oncogene) - "Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA or degradation by DZNep or MS1943 inhibited growth of LPCs and induced HPCs. As the proteasomal inhibitor MG132 induced EZH2 protein in HPCs, we evaluated ubiquitin pathway proteins in HPC vs LPCs. Biochemical assays and animal studies demonstrated that in LPCs, the E2-conjugating enzyme UBE2L6 depletes EZH2 protein in cooperation with UBR4, an E3 ligase, via ubiquitination at EZH2's K381 residue, and is downregulated in LPCs by UHRF1-mediated CpG methylation. Targeting UHRF1/UBE2L6/UBR4-mediated regulation of EZH2 offers potential for modulating the activity of this oncoprotein in contexts in which conventional EZH2 methyltransferase inhibitors are ineffective."

Journal • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • UHRF1

UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma (LCC 2023) - "Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA or EZH2 protein degradation by DZNep or MS1943 treatment significantly inhibited cell growth in LPCs by hampering ribosome biogenesis...As proteasomal inhibitor MG132 treatment induced EZH2 protein levels in HPCs we explored differentially regulated ubiquitin system proteins in HPC vs LPCs...UBE2L6 has been shown to be downregulated significantly in LPCs by UHRF1-mediated CpG methylation. Targeting this UHRF1/UBE2L6/UBR4 axis may be an optimal method to enforce the HPC state in melanoma in which conventional EZH2 inhibitors are ineffective."

Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • UHRF1

EZH2 Abundance Regulated by UHRF1/UBE2L6/UBR4 Ubiquitin System is the Potential Therapeutic Target to Trigger Pigmented Phenotype in Melanoma (LCC 2022) - "Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA strategy or DZNep, MS1943 that reduces EZH2 protein levels, significantly inhibited cell growth in LPCs by hampering ribosome biogenesis...Proteasomal inhibitor, MG132 treatment induced EZH2 protein levels in HPCs prompted us to look for differentially regulated ubiquitin system proteins in HPC vs LPCs...UBR4 cooperates with UBE2L6 to facilitate this ubiquitination process. Targeting UHRF1/UBE2L6/UBR4 axis can be a better treatment option to trigger HPC state in melanoma in which conventional EZH2 inhibitors are ineffective."

Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • EZH2 • UHRF1