: Simultaneous inhibition of cell cycle CDKs and transcriptional CDKs may provide a novel strategy for cancer therapy. Starting from a pan-CDK inhibitor, a series of novel 2-((4-substitutedphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives were synthesized and evaluated for their inhibition effects on cellular proliferation and CDK enzymatic activity. Several new derivatives exhibited significantly improved profiles in terms of in vitro antitumor potency, metabolic stability, and kinase selectivity. Further biological and in vivo pharmacokinetic evaluation confirmed that derivative 6m (LS-Q2) is a novel, orally bioavailable, and highly selective CDK4/9 inhibitor with potent antiproliferative activity against various tumor cells. Moreover, LS-Q2 exhibited significant synergistic antitumor eff ects when combined with the BET and Bcl-2 inhibitors. The discovery of LS-Q2 provides promising nextgeneration CDK inhibitor leads for the treatment of malignant solid tumors beyond breast cancer and highlights the potential of orally available and selective CDK4/9 inhibitors in cancer treatment. KEYWORDS: pyrrolo[2,3-d]pyrimidine derivatives, CDK4/9 inhibitors, synthesis, antiproliferation, structure−activity relationship T he global cancer burden remains heavy, despite breakthrough advances in antitumor therapy in recent decades. Treatment options for patients with advanced or unresectable tumors continue to be limited, especially for cancers with hidden onset and advanced diagnosis.
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