PAWI-2 has inhibitory effects on prostate cancer cells and pancreatic cancer stem cells through a novel mechanism of action involving inhibition of tubulin acetylation, BCL-2 and mitochondrial function. PAWI-2 inhibits cell proliferation of androgen-sensitive and androgen-insensitive prostate cancer cells (LNCaP and PC-3). Intraperitoneal administration of PAWI-2 in a PC-3 xenograft model resulted in the inhibition of of tumor growth by 49% compared with vehicle treated mice. PAWI-2 was demonstrated to synergize with the currently used clinical treatment, enzalutamide, to inhibit PCa cell viability in vitro and resensitized inhibition of PC-3 tumor growth in vivo. In addition, PAWI-2 was shown to potently inhibit cell viability and the self-renewal capacity of FGb3 cells, a validated cancer stem cell model (CSC). PAWI-2 inhibited b3-KRAS signalling independent of KRAS which is clinically significant in tumor progression. PAWI-2 overcame erlotinib (an EGFR inhibitor) resistance in FGB3 cells more potently than bortezomib. PAWI-2 repreasents a new approach to reverse tumor stemness that resensitizes CSC tumors to drug inhibition.
Systematic Name: 1-(4-((4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)sulfonyl)phenyl)pyrrolidin-2-one
Mol Wt: 371.46
Cheng J. et al. A Novel Small Molecule Inhibits Tumor Growth and Synergizes Effects of Enzalutamide on Prostate Cancers. J Pharmacol Exp Ther (2019), 371:703–712.
Cheng J. et al. PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin β3-KRASdependent pancreatic cancer stem cells. Nature Scientific Reports (2020) 10:9162 | https://doi.org/10.1038/s41598-020-65804-5.
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