title: 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.
abstract: 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.
authors.affiliation: Department of Discovery Chemistry, Discovery Oncology, Non-Clinical Drug Safety and Discovery Technologies, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. xin-jie.chu@roche.com
authors.forename: Xin-Jie
authors.initials: XJ
authors.lastname: Chu
authors.forename: Wanda
authors.initials: W
authors.lastname: DePinto
authors.forename: David
authors.initials: D
authors.lastname: Bartkovitz
authors.forename: Sung-Sau
authors.initials: SS
authors.lastname: So
authors.forename: Binh T
authors.initials: BT
authors.lastname: Vu
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Ding
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Ka
authors.initials: K
authors.lastname: Wang
authors.forename: Petra
authors.initials: P
authors.lastname: Goelzer
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yin
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Smith
authors.forename: Brian X
authors.initials: BX
authors.lastname: Higgins
authors.forename: Yingsi
authors.initials: Y
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiang
authors.forename: John
authors.initials: J
authors.lastname: Moliterni
authors.forename: Gerald
authors.initials: G
authors.lastname: Kaplan
authors.forename: Bradford
authors.initials: B
authors.lastname: Graves
authors.forename: Allen
authors.initials: A
authors.lastname: Lovey
authors.forename: Nader
authors.initials: N
authors.lastname: Fotouhi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: C515235:(4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl)(2,3-difluoro-6-methoxyphenyl)methanone; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011743:Pyrimidines; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases