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Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, x-ray crystal structure, SAR and anti-cancer activities

DOI: 10.1021/jm301475f DOI Help
PMID: 23301767 PMID Help

Authors: Hao Shao (University of Nottingham) , Shenhua Shi (University of Nottingham) , Shiliang Huang (University of Nottingham) , Alison Hole (University of Oxford) , Abdullahi Y Abbas (University of Nottingham) , Sonja Baumli (University of Oxford) , Xiangrui Liu (University of Nottingham) , Frankie Lam (University of Nottingham; University of South Australia) , David W. Foley (University of Nottingham) , Peter M. Fischer (University of Nottingham) , Martin Noble (University of Oxford) , Jane A. Endicott (University of Oxford; Newcastle University) , Chris Pepper (Cardiff University) , Shudong Wang (University of Nottingham; University of South Australia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 56 (3)

State: Published (Approved)
Published: January 2013

Open Access Open Access

Abstract: Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the C5-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,(34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B- and T-cells.

Journal Keywords: Cell; Tumor; Crystallography; X-Ray; Cyclin-Dependent; Drug; Antitumor; Humans; Magnetic; Models; Molecular; Protein; Pyrimidines; Spectrometry; Mass; Electrospray; Structure-Activity Relationship

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography