Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity.

The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K(i) > 10 microM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K(i) = 0.001, 0.003, and 0.001 microM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC(50) = 0.08 microM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

Stereotactic core needle biopsy of nonpalpable breast lesions using a conventional mammography unit with an add-on device.

OBJECTIVE: The purpose of this prospective study was to assess the accuracy of an add-on stereotactic unit for core needle biopsy of mammographic lesions. SUBJECTS AND METHODS. Between September 1994 and February 2001, 506 stereotactic core needle biopsies of mammographic lesions in 492 patients were performed in our center on a mammography unit with add-on stereotactic equipment. Of the initial 92 patients, 80 underwent stereotactic core needle biopsy and surgical excision simultaneously. In subsequent cases, surgical biopsy was performed after core biopsy in patients who had malignant or atypical histologic results or discordance between mammographic and pathologic findings. Follow-up mammography was advised for all patients whose core biopsy results were diagnosed as benign lesions. RESULTS: Histologic results for 506 lesions undergoing stereotactic core needle biopsy were as follows: 113 (22.3%) were malignant; 369 (72.9%), benign; and 24 (4.7%), atypical. Of 113 malignant lesions identified at stereotactic core needle biopsy, 111 were confirmed as malignant, whereas two showed no evidence of malignancy at surgical excision. Of 369 lesions diagnosed as benign at stereotactic core needle biopsy, 172 (46.6%) showed no change on follow-up mammography, 114 (30.9%) were lost to follow-up, and 83 (22%) underwent surgical excision. Of 24 lesions with atypical histology, 23 had surgical follow-up, six were malignant, nine were benign, and eight were confirmed as showing atypical histology. Stereotactic core needle biopsy of the 506 lesions was complicated by five (1.0%) cases of vasovagal attack and four (0.8%) cases of bleeding. The resulting sensitivity, specificity, and positive and negative predictive values were 98.3%, 93.0%, 86.0%, and 99.2% respectively. CONCLUSION: Biopsy with an add-on unit is safe, reliable, accurate, and cost-effective with results comparable to those reported for dedicated prone biopsy devices.