MYCi975

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.

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.

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.

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.

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.

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.