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Scientists at DDP have successfully designed and synthesized a series of novel anticancer agents based on NSAIDs



    Inflammation has received considerable attention for its role in the progression and aggressiveness of many cancers including NSCLC (nonsmall cell lung carcinoma). Many studies have shown the efficacy of NSAIDs (nonsteroidal antiinflammatory drugs) in animal models of cancer prevention, partly due their ability to block cyclooxygenase (COX) activity. Mechanistically, cyclooxygenases including COX-1 and especially COX-2 have been shown to be important in many stages of oncogenesis. The efficacies of COX-2 inhibitors in various animal models of cancer have also been characterized.

    Recently, scientists at DDP (Drug Discovery Pipeline) of GIBH (Guangzhou Institutes of Biomedicine and Health) have discovered a series of compounds which may have potential as a new class of chemotherapeutic agents that offer simplified dosing regimen with improved efficacy. In order to synthesis and evaluate more comprehensive anticancer agents from NSAIDs conjugates, a series of agents were designed and synthesized based on coupling of different NSAIDs with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokenetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers when both EGFR overexpression and inflammation play a direct role in disease progression.

    Overall, scientists at DDP have found a new series of conjugated compounds that may be used as a potentially simplified approach for treating cancers where both EGFR overexperssion and inflammation are involved. Their future studies will focus on the in vivo efficacy of the more potent coupled compounds in animal models of colon and lung cancer where inflammation is believed to be a significant contributing factor to disease progression.











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