R-stereoisomer of CBLC102 (quinacrine) has a potential to be a better anti-cancer agent than racemic CBLC102 due to its stronger p53- and NF-kB-modulating activities

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CBLC102, previously used as anti-malaria drug (quinacrine), is currently undergoing a phase II clinical trial against hormone refractory prostate cancer. CBLC102 has been defined as a potential anticancer agent for its ability to promote tumor cell death by simultaneous modulation of two major stress response pathways frequently deregulated in cancer: it can restore p53 activity in tumor cells with functionally impaired p53 pathway without causing DNA damage and inhibit NF-kB signaling in the cells with constitutively active NF-kB. As a stereoisomeric compound with one chiral center, CBLC102 represents a mixture of R- and S-enantiomers with potentially different biological and pharmacological properties. Pure R- and S-isomers of CBLC102 along with racemic CBLC102 (RS) were compared in p53 activation, NF-κB inhibition, cytotoxicity and DNA binding assays. R-CBLC102 happened to be more effective activator of p53 based on cellular reporter assay and p53 protein accumulation test. The same stereoisomer (R-CBLC102) was also a stronger inhibitor of NF-κB in tumor cells than S- or RS- CBLC102. Pathway modulating capacity of the molecule correlated with its anti-tumor cell cytotoxicity. We also demonstrated that R-CBLC102 binds to double-stranded DNA and RNA with higher affinity as revealed by competitive dialysis and DNA gel mobility shift assays. In total these results indicated that R-CBLC102 may have better anti-cancer potency than S-CBLC102. Currently anti-tumor efficacy of R- and S-CBLC102 is being tested in several mouse cancer models. Early results suggest that pure R-isomer is more efficacious anti-cancer agents than S-isomer or racemic CBLC102 and has a potential to become a new more powerful quinacrine-based anticancer drug.