MYCi361 is a MYC inhibitor with Kd value of 3.2μM. It engages MYC inside cells, disrupts MYC/MAX dimers, and impairs MYC-driven gene expression. MYCi361 suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy.
MYC proteins, including MYC, MYCL, and MYCN, play critical roles in tumorigenesis and therapeutic resistance. MYCi361 is an inhibitor of MYC that binds to intracellular MYC with a KD of 3.2 μM. Treatment of PC3 cells with MYCi361 (4–10 μM; 0.5 hr) led to significant thermal destabilization of MYC protein. Treatment of PC3 cells with MYCi361 (6 μM; 1 hr) led to disruption of the MYC/MAX interaction. MYCi361 (6 μM) decreased MYC protein stability by modulating MYC-Threonine 58 phosphorylation in PC3 cells. MYCi361 (6 μM; 24 h) also potently suppressed the expression of MYC target genes CDC25A and MYB in MYCT58A-expressing cells. MYCi361 inhibited the viability of MYC-dependent cancer cells including prostate cancer (MycCaP, LNCaP, and PC3), leukemia (MV4-11), lymphoma (HL-60 and P493-6), and neuroblastoma (SK-N-B2) with low-micromolar IC50 values. MYCi361 treatment of FVB mice bearing established MycCaP tumor allografts at 100 mg/kg/day induced tumor regression[2].
作用机制
MYCi361 binds to amino acids 366–378 of the MYC protein[2].
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