Cyclin dependent kinases (cdks) regulate the cell cycle, and their malfunctions are linked to tumor development, making cdk inhibitors a target for cancer chemotherapy. High-throughput screening (HTS) of our compound collection against cdk4/D1 identified A3915, a compound selective for the cdk family. A medicinal chemistry effort around A3915 was conducted to improve potency while maintaining selectivity, leading to the synthesis of indenopyrazoles, a new structural class of potent and selective cdk inhibitors. These compounds are selective for the cdk-related serine/threonine kinase family, active against transformed colon cell line HCT116, and have minimal cytotoxicity to normal fibroblasts. In vivo evaluation showed compound 5 had dose-dependent tumor growth inhibition activity in a human xenograft mouse model, with 43% inhibition at 30 mg/kg (intraperitoneal, once daily for 14 days) and no acute toxicity (all eight animals survived). This new class of cdk inhibitors exhibits in vitro and in vivo activity, and additional studies are underway to improve potency and optimize physical properties.