Structure-Activity-Relationship Exploration and Animal Validation of Novel Assembly Modulator Small Molecule Chemical Series with Pan-Cancer Selective Cytotoxicity

A novel class of protein assembly modulator chemical compounds that exhibit broad anti-tumor cytotoxicity has been recently described. Here we present a more detailed structure-activity-relationship exploration of the chemical series. PAV-0805, an advanced analog, was found to be safe in mice at 10mg/kg and nontoxic to normal human peripheral blood mononuclear cells (PBMC) cells. PAV-0805 has demonstrated broad anti-cancer activity in the NCI-60 cell lines, including against a diversity of brain, breast, colon, lung, ovarian prostate, renal, and skin cancers, and leukemias. In the aggressive 4T1 mouse allograft breast cancer model, PAV-0805 was effective in reducing tumor growth and metastasis when treatment was initiated early (primary tumor volume of 50mm ³ ) or late (primary tumor volume of 500mm ³ ), and under both treatment conditions showed inhibition of both tumor growth and metastasis comparable to paclitaxel. The novel multi-protein complex targeted by these compounds is enriched in gene products involved in the cancer hallmarks of resisting cell death and reprogramming energy metabolism.