Benzofuranyl-pyrazole as a Novel Scaffold for In Vitro and In Vivo Potent Anticancer Therapeutics That Directly Disrupt the ‘Undruggable’ MYC Oncogene and Potentiate Immune Checkpoint Blockage

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.