Applying molecular hybridization to design a new class of pyrazolo[3,4-d]pyrimidines as Src inhibitors active in hepatocellular carcinoma

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Hepatocellular carcinoma (HCC) is the most common type of liver solid tumor and the second leading cause of cancer-related deaths worldwide. Although new treatment options have been recently approved, the development of tumor resistance and the poor prognosis for advanced HCC make the current standard of care unsatisfying. In this scenario, the non-receptor tyrosine kinase (TK) c-Src emerged as a promising target for developing new anti-HCC agents. Our group reported a large library of pyrazolo[3,4- d ]pyrimidines active as potent c-Src inhibitors. Starting from these data, we applied a molecular hybridization approach to combine the in-house pyrazolo[3,4- d ]pyrimidine SI192 with the approved TK inhibitor (TKI) dasatinib, with the aim of identifying a new generation of Src inhibitors. Enzymatic results prompted us to design second-generation compounds with a better binding profile based on a hit optimization protocol comprised of molecular modeling and on-paper rational design. This investigation led to the identification of a few nanomolar Src inhibitors active toward two HCC cell lines (HepG2 and HUH-7) selected according to their high and low c-Src expression, respectively. In particular, 7e showed an IC 50 value of 0.7 nM toward Src and a relevant antiproliferative efficacy on HepG2 cells after 72h (IC 50 = 2.47 μM). Furthermore, 7e exhibited a cytotoxic profile better than dasatinib. The ADME profile suggested that 7e deserves further investigation as a promising TKI in cancer therapies. Finally, 7e ′s ability to inhibit HepG2 cell proliferation, elicit an irreversible cytotoxic effect, arrest cellular migration, and induce apoptotic-mediated cell death was assessed. • Synthesis of new generation hybrid pyrazolo[3,4- d ]pyrimidines. • In vitro evaluation against c-Src. • Hit optimization based on molecular modeling and on-paper rational design. • Identification of nanomolar Src inhibitors active in hepatocellular carcinoma (HCC). • Characterization of the ADME profile of the most promising derivatives.

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