MYCi975

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Consequently, MYCi975 synergistically sensitized resistant prostate cancer cells to enzalutamide and estrogen receptor-positive breast cancer cells to 4-hydroxytamoxifen. Our results demonstrate that MYCi975 selectively inhibits MYC target gene expression and provide a mechanistic rationale for potential combination therapies.