MYCi-975

Targeting the 'undruggable' MYC oncogene remains a challenging objective. Despite substantial research efforts, a majority of MYC direct inhibitors discovered so far lack in vivo efficacy. Herein, benzofuranyl-pyrazole has been identified as a structurally novel scaffold directly disrupting MYC function. Among the final compounds, 15 displayed 10-fold enhanced antiproliferative activity over MYCi975, a well-established MYC inhibitor, against PC-3 cells. Besides, it exhibited low micromolar to submicromolar activities against 14 other neoplastic cell lines. Its direct perturbation of MYC function was confirmed by the obstruction of MYC/MAX interaction in Co-IP and AlphaLISA assays. Moreover, it decreased MYC thermal stability, triggered MYC degradation, and impaired expression of MYC-responsive luciferase. 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.

MYC is one of the most frequently altered genes in cancer with an estimated 70% prevalence of deregulation. Deregulated MYC is believed to promote cancer formation/progression via multiple mechanisms including tumour cell intrinsic mechanisms, altering the tumour microenvironment and promoting host immune suppression. Owing to the high prevalence of alterations and its causative role in tumorigenesis, MYC is a highly attractive target for new anticancer therapies. However, as MYC lacks a readily identifiably pocket for potential low molecular weight inhibitors and is predominantly located in the cell nucleus, it has proved difficult to target using standard pharmacological approaches. Recently, however, these problems appear to have been successfully resolved, with the discovery of promising anti-MYC compounds such as Omomyc or MYCi975. Both Omomyc and MYCi975 exhibit anti-cancer activity in several different animal models, with apparently little short-term toxicity. Furthermore, consistent with the ability of MYC to promote a pro-tumour microenvironment and induce immune evasion, treatment with Omomyc or MYCi975 was shown to increase uptake of anti-tumour lymphocytes and enhance response to immunotherapy. Currently, at least five anti-MYC compounds are being evaluated for potential anti-cancer activity in clinical trials. 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.