Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia

Nowadays, the simultaneous inhibition
of two or more pathways plays
an increasingly important role in cancer treatment due to the complex
and diverse pathogenesis of cancer, and the combination of the cyclin-dependent
kinase 6 (CDK6) inhibitor and PIM1 inhibitor was found to generate
synergistic effects in acute myeloid leukemia (AML) treatment. Therefore,
we discovered a novel lead 1 targeting CDK6/PIM1 via pharmacophore-based and structure-based virtual screening,
synthesized five different series of new derivates, and obtained a
potent and balanced dual CDK6/PIM1 inhibitor 51, which
showed high kinase selectivity. Meanwhile, 51 displayed
an excellent safety profile and great pharmacokinetic properties.
Furthermore, 51 displayed stronger potency in reducing
the burden of AML than palbociclib and SMI-4a in vivo. In summary, we offered a new direction for AML treatment and provided
a great lead compound for AML preclinical studies.