Novel MYC-Targeting Drug Is Effective in Mouse Prostate Cancer Models

Although MYC proteins are important in cancer development and treatment resistance, efforts to develop drugs targeting them have been largely unsuccessful. Han and colleagues approached this problem by using an in silico screen to develop a library of possible MYC-binding small molecules with drug-like properties, then narrowing the list using biochemical assays, such as tests of whether each drug candidate could disrupt MYC–MAX–DNA complex formation. Further shortening the list of options, rapid in vivo screening using a mouse model of prostate cancer was incorporated into the strategy, followed by several biochemical assays to test for optimal drug properties. This series of tests identified a chemical dubbed 361 as the top candidate for further testing. Additional experiments suggested that 361 destabilizes MYC by increasing phosphorylation of MYC's T58; also, the drug appears to disrupt MYC–MAX interactions and reduce the expression of some MYC target genes. Treatment with 361 resulted in tumor regression in a mouse model of prostate cancer, and this effect was more pronounced in immunocompetent mice than in immunocompromised mice, suggesting that a functional immune system is required for optimal effects. There was evidence that 361 treatment stimulated an immune response to the tumor, exemplified by increased tumor infiltration of CD3⁺ T cells and upregulation of PD-L1 on tumor cells. Correspondingly, immunocompetent mice exhibited greater suppression of tumor growth when treated with 361 followed by anti–PD-1 than mice treated with either agent alone, indicating that combination treatment with MYC inhibitors and immune checkpoint blockade may be a promising strategy. Although 361 provided a useful starting point in the search for MYC-inhibiting drugs, it also had unwanted qualities, such as a narrow therapeutic index. Several analogues were thus developed, yielding one, called 975, which had the desirable qualities of 361 with reduced toxicity. The 975 analogue reduced the viability of cancer cells, decreased MYC-target transcription, and exhibited antitumor efficacy that, as with 361, was enhanced by immunocompetence. This study demonstrates that MYC may not be undruggable, as has been suggested, and that therapies targeting MYC—perhaps in conjunction with immune checkpoint blockade—may be on the horizon.

Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, et al. Small-molecule MYC inhibitors suppress tumor growth and enhance immunotherapy. Cancer Cell 2019;36:483–97.e15.

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