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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 50mm3) or late (primary tumor volume of 500mm3), 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.
Competing Interest Statement
VRL is CEO and AFL COO of Prosetta Biosciences, Inc.