Discovery of a Novel Dihydroisoquinolinone Derivative as a Potent CDK9 Inhibitor Capable of Overcoming L156F Mutant for the Treatment of Hematologic Malignancies

Hematologic malignancies represent the most prevalent type of malignant cancers associated with significant morbidity and mortality rates. Given CDK9's extensive crosstalk with various signaling pathways and its crucial role in maintaining stem cell phenotypes, it emerges as a promising therapeutic target for hematologic malignancies. Despite ongoing efforts, resistance remains a ubiquitous challenge and significant limitation in the management of these malignancies. Here, we discovered a novel potent and selective inhibitor (14) of both CDK9 wild-type and L156F mutant, which inhibited p-Ser2 RNA Pol II, cMYC, and Mcl-1, ultimately triggering Apoptosis of hematological Cancer cells. In vitro studies further revealed that 14 could efficiently suppress the proliferation of a diverse range of hematological Cancer cell lines. Additionally, the in vivo efficacies have been demonstrated in different genetic background hematologic Cancer cell-derived mice models. Together, these findings highlight the promising potential of this novel CDK9 Inhibitor in the treatment of hematological malignancies.