Hepatocellular carcinoma (HCC) is one of the most difficulty to treat cancer type and has a very low survival rate. Although early-stage HCC can be treated via surgical resection, advanced HCC has limited therapeutic options. Currently, sorafenib, a tyrosine kinase inhibitor remains a frontline drug for systemic treatment. Poor prognosis and high chance of recurrence of HCC highlight the importance and pressing need for new classes of chemotherapeutics. We have investigated a unique class of aryl-thiazoline-sulfonamides as potential anticancer agents for HCC. Initial structure-based investigation has led us to identify two new compounds with low micromolar anticancer activity against various liver cancer cell lines. Further mechanistic evaluation confirmed that the compounds are targeting cyclin-dependent kinases (CDK), which are a unique class of proteins and they play a critical role in regulating cell division. More specifically, our synthetic compounds selectively inhibited CDK4 and CDK6 isoforms. Current literature provides key evidence that CDK4/6 inhibitors are promising class of chemotherapeutics for the treatment of HCC. Moreover, clinically used CDK4/6 inhibitors have been demonstrated to be effective against HCC. Based on our preliminary results, we have identified a series of small molecules that inhibited an important druggable target. Our current efforts are focused on further optimizing the chemical scaffold to improve anticancer activity, and gaining more mechanistic insights.

Discovery of a new class of aryl-thiazoline sulfonamides as CDK4/6 inhibitors and anticancer agents against hepatocellular carcinoma

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ACS Fall 2022

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