MYCi975 / Northwestern University Feinberg School of Medicine - LARVOL DELTA

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 • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CALR • ITGAM • MYC • PTPRC • S100A9

Defining the functional role and potential as an immunotherapeutic target of ALCAM in neuroblastoma. (PubMed, Mol Cancer Ther) - "Treatment with the MYC(N)/MAX dimerization inhibitor MYCi975 reduced ALCAM expression by immunoblotting and luciferase signal from the ALCAM promoter. Finally, as ALCAM is expressed in several normal tissues, we investigated an ALCAM-targeted conditionally activated antibody drug conjugate (ADC), CX-2009 (praluzatamab ravtansine), which delayed tumor growth in two out of three PDX models. Together, these findings credential ALCAM as an immunotherapeutic target in neuroblastoma."

IO biomarker • Journal • Neuroblastoma • Oncology • Pain • Pediatrics • Solid Tumor • ALCAM • MYCN

PHARMACOLOGICAL MANIPULATION OF MYC PHOSPHORYLATION IN PSC ANIMALS MODELS DRIVES CHOLANGIOCYTE CELL FATE (AASLD 2025) - "Our in vitro studies also revealed that pharmacologic inhibition of MYC [with MYCi975 (MYCi)] promoted cholangiocyte senescence while inhibition of GSK3 [with CHIR99021 (CHIR)] drove cholangiocyte proliferation, results identifying dual kinase mediators of cholangiocyte cell fate... The data demonstrate that MYC is a driver of cholangiocyte proliferation in PSC animal models and identify the kinase mediators that determines cholangiocyte cell fate. Together, the results support the notion that MYC is a "molecular switch" in that determines cholangiocyte responses to stress."

Preclinical • Fibrosis • Immunology • ABCB4 • KRT7 • PCNA

MYC as a Target for Cancer Treatment: from Undruggable to Druggable? (PubMed, Target Oncol) - "Recently, however, these problems appear to have been successfully resolved, with the discovery of promising anti-MYC compounds such as Omomyc or MYCi975. Results from a phase I trial with OMO-103 (a form of Omomyc) suggest that the inhibitor is well tolerated, with most of its adverse effects being at grade 1 level. Evidence of target inhibition was the finding of decreased expression of multiple MYC regulated genes."

IO biomarker • Journal • Review • Oncology

Benzofuranyl-pyrazole as a Novel Scaffold for In Vitro and In Vivo Potent Anticancer Therapeutics That Directly Disrupt the 'Undruggable' MYC Oncogene and Potentiate Immune Checkpoint Blockage. (PubMed, J Med Chem) - "Notably, 15 potently delayed tumor growth and outperformed MYCi975 in a mouse allograft model, even when administered every other day. Meanwhile, it synergized with a small-molecule immune checkpoint inhibitor in vivo, highlighting its potential application in immunotherapy."

Checkpoint inhibition • IO biomarker • Journal • Preclinical • Oncology • MYC

A Small Molecule Selectively Targets N-Myc to Suppress Neuroblastoma Cancer Progression. (PubMed, Int J Biol Sci) - "Notably, N78 demonstrates acceptable tolerability and induces significantly enhanced tumor regression in vivo compared to Myci975, a leading candidate among c-Myc/N-Myc inhibitors. Mechanistically, N78 promotes the phosphorylation of N-Myc at threonine-58, leading to its degradation via the ubiquitin-proteasomal pathway. This study presents the first selective N-Myc inhibitor N78, and highlights the promise of small-molecule N-Myc inhibitors as both chemical probes and potential anti-cancer therapies for neuroblastoma."

Journal • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • Targeted Protein Degradation • MYC • MYCN

Reinforced Dynamics platform empowers the discovery of novel inhibitors and degraders of transcription factor c-Myc (ACS-Fall 2025) - "Furthermore, structure-based optimization of the lead compound MYCi975 yielded c-Myc degraders with nanomolar cellular potency...Our work establishes a paradigm for drugging "undruggable" transcription factors by leveraging dynamic conformational landscapes, with broad implications for targeting PPIs in oncology. The catalytic degraders derived represent the first c-Myc-targeted agents with both direct binding validation and submicromolar efficacy, offering a promising strategy to address the long-standing therapeutic challenges in MYC-driven cancers."

MYC

Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors. (PubMed, Sci Adv) - "We have developed and characterized a small-molecule MYC inhibitor named MYCi975...Additionally, a wide range of tumor cells with lower complex I expression showed increased MYC dependency. These results indicate that metabolic adaptation to MYC inhibition exposes a targetable weakness at complex I and provide a rational strategy for combination therapy with emerging MYC inhibitors."

Journal • Oncology • CD8

Twist1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of Twist1. (PubMed, Neoplasia) - "Altogether, these results indicate that the Twist1 transactivation domain is required for Twist1-dependent acceleration of lung tumorigenesis via MYC and nominate MYCi975 as a means to activate latent OIS programs. MYC targeting strategies could limit pro-tumorigenic programs and serve as a therapeutic for TWIST1-overexpressing NSCLCs."

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

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.Keywords: Cells Natural Killer Cells; Molecules Cell Surface Molecules MHC Transcription Factors; Processes Cytotoxicity"

IO biomarker • Late-breaking abstract • Tumor mutational burden • 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