CBL0137 is a suppressor of the histone chaperone FACT, which is crucial for chromatin transcription. By downregulating NF-kappaB and activating p53, CBL0137 effectively reinstates acetylation and trimethylation of histone H3. Its role as an anticancer agent is further underscored by its ability to trigger apoptosis in cancer cells[2].
体内研究
Further evidence of CBL0137’s antitumor efficacy is observed in preclinical models. Monotherapy or combination therapy with gemcitabine showcases significant antitumor effects, evidenced by extensive necrotic areas, a multitude of apoptotic bodies, and a marked decrease in tumor cell viability. Interestingly, doses ranging between 50 to 60 mg/kg of CBL0137 augment gemcitabine's antitumor action comparably to the maximum tolerated dose (MTD) of 90 mg/kg, indicating no significant differences among these combination therapies. This potent activity stems from CBL0137’s ability to impair FACT functionality by diminishing the active FACT pool necessary for transcription elongation[2].
Moreover, CBL0137, administered orally at a safe dosage of 30 mg/kg per day following a 5 days on/2 days off regimen, effectively inhibits tumor growth in xenograft models of colon (DLD-1), renal cell carcinoma (Caki-1), melanoma (Mel-7), and transplanted patient-derived pancreatic ductal adenocarcinoma samples[3]. Such widespread anticancer efficacy exemplifies CBL0137’s potential as a highly versatile and potent therapeutic option in the treatment of cancer.
体外研究
CBL0137's capability to entirely eliminate viable cells at dosages exceeding 2.5 μM has been documented. When used alongside gemcitabine, it notably lowers the colony formation of MiaPaCa-2 cells and even those of gemcitabine-resistant PANC-1 cells. By reducing the levels of RRM1 and RRM2 proteins and mRNA in a concentration-dependent manner, CBL0137 enhances the efficacy of gemcitabine, specifically by obstructing the drug-induced upregulation of these critical enzymes for DNA replication and repair[2].
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