S

CO2 Glu-81

Leu-83

FIGURE 9.16 Binding of flavopiridol to CDKs.

Alvocidib (flavopiridol, HMR-1275) is a semi-synthetic flavone related to a natural product extracted from two Indian plants (Amoora rohituka and Dysoxylum binectariferum), and was the first CDK inhibitor to reach human clinical trials in patients with NSCLC, in combination with paclitaxel. Flavopiridol is a nonselective CDK inhibitor, thus explaining G1 and G2 arrest, and is also an inhibitor of transcription.59 In spite of highly promising Phase I trials in a variety of cancers, the results of Phase II studies were rather disappointing in most cases, although encouraging results found in one of these studies60 have prompted a Phase III study for the treatment of metastatic lung carcinoma, in combination with other chemotherapeutic agents. Flavopiridol binds to the ATP site, with the benzopyran ring lying in the adenine binding region, establishing the hydrogen bonds shown in Fig. 9.16.61

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