MYCi975 / Northwestern University Feinberg School of Medicine - LARVOL DELTA

Investigating the immunological effect of MYCN depletion in MYCN-amplified neuroblastoma (IMMUNOLOGY 2025) - "This upregulation appeared specific to MYCN depletion, as it was absent in cells treated with doxorubicin or etoposide. MYCi975 also enhanced NK-cell mediated killing of MYCN -amplified cells in the presence of dinutuximab, an FDA-approved anti-GD2 monoclonal antibody for high-risk neuroblastoma, and reduced secretion of the immunosuppressive cytokine IGFBP-2. These findings reveal a mechanism by which MYCN influences anti-tumor immunity and suggest a broader role in TIME modulation, providing a foundation for exploring the therapeutic potential of HLA-G and DR5 co-upregulation with MYCN targeting."

IO biomarker • Late-breaking abstract • Tumor mutational burden • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • IGFBP2 • MYCN • TMB • TNFRSF10B

Combinatorial treatment with small molecule inhibitors C26-A6 and MYCi975 in hepatocellular carcinoma (HCC) (AACR 2025) - "MYCi975 inhibited cell proliferation, while C26-A6 inhibited cell invasion indicating that in an in vivo setting C26-A6 and MYCi975 combination might inhibit both primary and metastatic tumors and the combination might exert a synergistic inhibitory effect compared to either agent alone. Studies are ongoing to evaluate in vivo therapeutic efficacy of the treatment and elucidate the underlying mechanism mediating the effects of the combination treatment."

Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • E2F2 • FOXM1 • MTDH • MYC • STAT3

Impact of MYCN inhibition on lineage state and GD2 expression in neuroblastoma (AACR 2025) - "However, GD2 is downregulated in resistant cells with implications for the relative timing of MYCN-targeting and GD2 targeting therapies. Ongoing work will be presented on transcriptomic changes after MYCi975 treatment and in resistant cells."

IO biomarker • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • MYCN

Temporal regulation of c-Myc in endocycling cancer cells facilitates mitotic bypass in response to chemotherapy (AACR 2025) - "Myc protein levels can be rescued using the proteasome inhibitor, MG132, demonstrating that the low Myc status is driven by proteasomal degradation. To test if Myc degradation serves a mechanistic function, the small molecule inhibitor, MYCi975, was used to inhibit Myc activity at various points in the mitotic cell cycle...This data supports our hypothesis that the low-Myc status of endocycling cells plays a mechanistic role in permitting mitotic bypass through premature loss of activity in G2. Preliminary data suggests that rescuing Myc activity will force mitotic entry producing mitotic progeny cells."

Oncology • MYC

Impact of TWIST1 Transactivation Domain towards Oncogene-Induced Senescence Suppression in Non-Small Cell Lung Cancer (ASTRO 2024) - "Materials/ We created a novel genetically engineered mouse model (GEMM) allowing tetracycline-inducible expression in the lung epithelium (via lung specific CCSP-reverse tetracycline transactivator (C)) of KRasG12D (R) with Twist1wt (T) or with Twist1F191G transactivation-null mutant (F). Altogether, these results suggest that TWIST1 may suppress OIS via MYC signaling and nominate MYCi975 as a means to activate latent OIS programs. MYC inhibiting strategies could serve as a therapeutic sensitizer for TWIST1-expressing NSCLC. This work and our future studies on TWIST1 on the control of OIS, O-GlcNAcylation, and radioresistance mechanisms may help to identify new potential NSCLC therapeutic strategies."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • TWIST1

Bone Marrow Immune Ecosystem Shapes Acquired Daratumumab Resistance in Plasma Cell Myeloma (IMW 2024) - "MYCi975 reversed resistance to dara-mediate ADCC. Mechanisms underlying acquired daratumumab resistance are complex involving crosstalk between immune cells and neoplastic plasma cells. Increased activation of MYC may be an important mechanism promoting acquired daratumumab resistance."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Plasmacytoma • CCR7 • CD8 • GZMK • IFNG • MYC • PTPRC • SDC1

The bone marrow immune ecosystem shapes acquired resistance to daratumumab in plasma cell myeloma (ESMO 2024) - "Funding: Sun Yat-sen University Start-Up Funding. Increased activation of MYC following anti-cancer stress may be an important mechanism promoting acquired dara resistance."

Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • Plasmacytoma • CD8 • GZMK • IFNG • MYC • PTPRC • SDC1

Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer. (PubMed, Cancer Res) - "Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared to either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for HNSCC patients, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Targeted Protein Degradation • GLS1 • MYC • SNAI2 • USP1

Directly Suppressing MYC Function with Novel Alkynyl-Substituted Phenylpyrazole Derivatives that Induce Protein Degradation and Perturb MYC/MAX Interaction. (PubMed, J Med Chem) - "Moreover, 37 demonstrated enhanced therapeutic efficacy over MYCi975 in a mouse allograft model of prostate cancer. Overall, 37 deserves further development for exploring MYC-targeting cancer therapeutics."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation

BONE MARROW ECOSYSTEMS SHAPE SECONDARY RESISTANCE TO ANTI-CD38 TREATMENT IN MULTIPLE MYELOMA (EHA 2024) - "Lactate dehydrogenase release testing revealed thatcMYC inhibitor MYCi975 displayed the cytotoxicity to daratumumab (Dara) acquired resistant plasma cells andreversed the resistance to Dara (Figure n). The results show that quantity and spatial variation of CD8+T cells, NK cells, and B cells are the predominantfactors contributing to acquired resistance. The increased activation of MYC and the related elevated biologicaland metabolic programs following anti-tumor stress may be a key mechanism promoting acquired resistance."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • C1QB • CD8 • GZMK • IFNG • KLRC1 • MYC • PLPP5 • PTPRC • SDC1 • TRGC2

MYC CONTROLS STEMNESS AND CHEMORESISTANCE IN HUMAN COLONIC TUMOROIDS (DDW 2024) - "We pretreated tumoroids with MYCi975 prior to 5-fluorouracil (5-FU) treatment to assess the potential use of this MYC inhibitor for combinatorial therapy. We found that MYC depletion reduced stem cell transcripts including LGR5 reduced Ki67+ cells and diminished tumoroid growth and viability. Pre-treating tumoroids with MYCi975 sensitized them to 5-FU chemotherapy. This work provides new insight into the role of MYC in the chemoresistance of human colonic tumoroids."

Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • MYC

MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance. (PubMed, Clin Cancer Res) - "Our study supports the concept that MYC represents an Achille's heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs."

Immunomodulating • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • CD8 • CRBN • IKZF1 • IKZF3 • IRF4 • MYC

TWIST1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of TWIST1 (AACR 2024) - "Furthermore, TWIST1wt expression with HRasG12V modulated MYC downstream targets and the inhibition of MYC activity using the novel MYC inhibitor MYCi975 in HBEC-HRasG12V-TWIST1wt also rescued OIS induction...In this context, MYC inhibiting strategies could serve as a therapeutic sensitizer for TWIST1-positive NSCLC. This work and our future studies on TWIST1 toward the control of OIS, O-GlcNAcylation and of mechanisms of radioresistance may help to identify new potential NSCLC therapeutic strategies."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • TWIST1

Proffered Paper: Targeting MYC with the Novel Molecular Glue, GT19630 for the Treatment of Breast Cancer (EACR-AACR 2024) - "IC50 values for GT19630 were an order of magnitude lower than that for 3 previously described MYC-MAX antagonists, i.e., MYCi975 (p < 0.0001), MYCMI-6 (p < 0.0001), or GT19077 (p < 0.0001), i.e., GT19630 was a significantly more potent inhibitor than the 3 MYC-MAX antagonist investigated. Finally, we found that GT19630 degraded the negative immune checkpoint protein B7-H3 which has been implicated in immune evasion. Conclusion Based on our findings, we conclude that GT19630 should be an effective inhibitor of breast cancer cell growth."

Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CD276 • GSPT1 • MYC

Pharmacological inhibition of MYC to mitigate chemoresistance in preclinical models of squamous cell carcinoma. (PubMed, Theranostics) - "Mechanistically, MYCi975 induced the DNA damage response and activated the cGAS-STING-IRF3 signaling pathway to increase CD8 T cell-recruiting chemokines. Our findings suggested that targeting MYC might eliminate CSCs, prevent metastasis, and activate antitumor immunity to overcome cisplatin resistance in HNSCC."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • MYC • STING

The PP2A-B56α Heterocomplex Regulates Response to Venetoclax Plus Azacitidine Treatment in AML (ASH 2023) - "Of note, treatment of HL-60 B56α KD cells with the MYC inhibitor MYCi975 rescued the VEN+Aza synergy seen in these cells, confirming the relevance of MYC degradation to VEN+Aza response. Interestingly, a novel small molecular glue (PMG) developed by our group, which specifically stabilizes the PP2A-B56α complex, enhanced VEN plus Aza response in vitro; however, this triple therapy did not work in HL-60 B56α KD cells and we observed a clearly decrease in MYC protein expression upon the triple therapy only in HL-60 B56α WT cells, supporting the rationale to translate these novel PMGs into the clinic. Altogether, our data suggest that PP2A-B56α might have an important role in VEN plus Aza treatment response through the regulation of MYC degradation."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • BCL2 • CDKN1A • MYC • PPP2R2A

MYC-Alarmin Axis As a Novel Oncogenic Driver in a Subgroup of Triple Negative Myeloproliferative Neoplasms (ASH 2023) - "MYCi975, a small molecule that inhibits MYC, reduced MYC and S100a9 protein levels in BM and spleen cells...In summary, our studies are the first to describe an oncogenic role of MYC in MF pathogenesis, where MYC provokes an alarmin-driven inflammatory circuit, and where the MYC-S100A9 axis represents a therapeutic vulnerability for TN-MF patients. Accordingly, our results provide a strong rationale for testing agents targeting MYC or S100A9 in early phase clinical trials in MPNs having increased MYC levels or activity."

Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation • CALR • ITGAM • MYC • PTPRC • S100A9

Effects of MYC Inhibitors on the Growth of Acute Leukaemia Cells. (PubMed, Anticancer Res) - "MYC inhibitors appear to be novel molecular-targeted drugs against acute leukaemia, including NOTCH1-mutated T-ALL. However, it is necessary to elucidate the precise molecular mechanisms of these effects before clinical use."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • CDKN1A • HES1 • MAX • MYC • NOTCH1

Degradation of MYC by the mutant p53 reactivator drug, COTI-2 in breast cancer cells. (PubMed, Invest New Drugs) - "Proteasome-mediated degradation was determined using the proteasome, inhibitor MG-132, while MYC half-life was measured using pulse chase experiments in the presence of cycloheximide. Co-treatment with COTI-2 and the MYC inhibitor, MYCi975 resulted in synergistic growth inhibition in all 4 mutant p53 cell lines investigated. The dual ability of COTI-2 to reactivate mutant p53 and degrade MYC should enable this compound to have broad application as an anticancer drug."

Journal • Breast Cancer • Oncology • Solid Tumor • TP53

Inhibition of class IIa HDACs potentiates MYC inhibitor-driven cytotoxicity by inducing MYC depletion and oxidative stress in non-small cell lung cancer (AACR 2023) - "Recently, two direct MYC inhibiting agents with improved in vivo efficacy and tolerability, MYCi975 and Omomyc, have been developed...Expanding these studies to in vivo models, we discern that combination MYC and class IIa HDAC inhibition significantly reduced tumor burden in a patient-derived xenograft model of human NSCLC. In summary, we define here a novel drug paradigm combining MYC and class IIa HDAC inhibitors, which potentiates anti-tumor efficacy in NSCLC via MYC depletion and oxidative stress."

Oxidative stress • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AVEN • EGFR • HDAC5 • HDAC9 • MYC • STK11

ALCAM promotes neuroblastoma proliferation, migration, and immune evasion (AACR 2023) - "We probed the effects of the MYC(N)-MAX disrupter MYCi975 on ALCAM expression using immunoblotting... ALCAM is overexpressed in neuroblastoma and its expression is driven, at least in part, by MYC(N). ALCAM is a mediator of cellular proliferation and migration and may contribute to immune evasion by inhibiting T cell activation. Ongoing in vivo studies will characterize the effects of ALCAM depletion on tumor growth and metastasis."

IO biomarker • CNS Tumor • Genito-urinary Cancer • Lung Cancer • Neuroblastoma • Neuroendocrine Tumor • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • ALCAM • CD4 • CD69 • CD8 • IFNG • MYCN • TNFA

Transcriptional Rewiring and Therapeutic Resistance in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia (ASH 2022) - "We found potent inhibition of Ph-like ALL viability in vitro when combining a new MYC inhibitor MYCi975 (Han Cancer Cell 2019) with ruxolitinib at sub-IC50 doses. Our findings suggest that Ph-like ALL cells can resist ruxolitinib treatment via TKI-induced gene regulatory network rewiring that leads to altered apoptosis and dormant/senescent states. Ongoing studies are investigating the therapeutic potential of targeting these dormant cells using inhibitors such as venetoclax, senolytics, or novel MYC inhibitors, which may have translational potential for future combinatorial treatment of patients with Ph-like ALL."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • CRLF2 • MYC

MYC Driven Immune Suppression in Group 3 Medulloblastoma (SNO 2022) - "In two orthotopic mouse models of MYC-driven medulloblastoma, MYCi975 displayed anti-tumoral effects at the primary site and the metastatic compartment. Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC-medulloblastoma and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses."

IO biomarker • Brain Cancer • Glioblastoma • Immune Modulation • Inflammation • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • CALR • IFNG • MYC • SIRPA

Therapeutic Targeting of MYC in Head and Neck Squamous Cell Carcinoma. (PubMed, Oncoimmunology) - "MYC inhibitor 975 (MYCi975), inhibited HNSCC growth in both cell line-derived xenograft and syngeneic murine models...High expression of MYC combined with a low level of infiltrated CD8 T cell in HNSCC correlated with poor prognosis. These results suggested the potential of small-molecule MYC inhibitors as anti-cancer therapeutic agents in HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • MYC

MYC as a therapeutic target for the treatment of triple-negative breast cancer: preclinical investigations with the novel MYC inhibitor, MYCi975. (PubMed, Breast Cancer Res Treat) - "Our findings open the possibility of targeting MYC for the treatment of TNBC. Based on our results, we suggest that trials use a combination of MYCi975 and either docetaxel or doxorubicin and include MYC as a putative therapy predictive biomarker."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer