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Synthesis, SAR and biological evaluation of 1,6-disubstituted-1H-pyrazolo[3,4-d]pyrimidines as dual inhibitors of Aurora kinases and CDK1

, : Synthesis, SAR and biological evaluation of 1,6-disubstituted-1H-pyrazolo[3,4-d]pyrimidines as dual inhibitors of Aurora kinases and CDK1. Bioorganic & Medicinal Chemistry Letters 22(5): 2070-2074

Since the early 2000s, the Aurora kinases have become major targets of oncology drug discovery particularly Aurora-A and Aurora-B kinases (AKA/AKB) for which the selective inhibition in cells lead to different phenotypes. In addition to targeting these Aurora kinases involved in mitosis, CDK1 has been added as a primary inhibition target in hopes of enhancing the cytotoxicity of our chemotypes harboring the pyrazolopyrimidine core. SAR optimization of this series using the AKA, AKB and CDK1 biochemical assays led to the discovery of the compound 7h which combines strong potency against the 3 kinases with an acceptable microsomal stability. Finally, switching from a primary amide to a two-substituted pyrrolidine amide gave rise to compound 15a which exhibited the desired AKA/CDK1 inhibition phenotype in cells but showed moderate activity in animal models using HCT116 tumor cell lines.


PMID: 22326168

DOI: 10.1016/j.bmcl.2012.01.019

Other references

Puetz, Andreas., 2002: A contribution towards the knowledge of the Byrrhidae of Japan Coleoptera Ein Beitrag zur Kenntnis der Pillenkaefer Japans Coleoptera Byrrhidae. Entomologische Zeitschrift. 17 Juni; 1126: 184-190

Sweetman, C., 1995: Editorial. This editorial introduces a journal devoted to the issues surrounding women and their rights. As the development debate moves from women's need to their rights and to an understanding of the cultural roots of legal systems and the effects of...

Dolinova, J.; Klanova, J.; Klan, P., 2005: Photodegradation of organic pollutants adsorbed on spruce needles. Photodegradation of selected organic pollutants, 2,2-bis(4-chlorobiphenyl)-1,1,1-trichloroethane (p,p'-DDT), 4-chlorobiphenyl (PCB 3), 2,4-dichlorobiphenyl (PCB 7), 4,4'-dichlorobiphenyl (PCB 15), and 2,2',4,4',5,5'-hexach...

Ma, X.Xue.; Ito, T.; Chongtrakool, P.; Hiramatsu, K., 2006: Predominance of clones carrying Panton-Valentine leukocidin genes among methicillin-resistant Staphylococcus aureus strains isolated in Japanese hospitals from 1979 to 1985. We examined 97 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated between 1979 and 1985, the period of time when the appearance of MRSA strains increased, and we determined that these strains are distinct from the MRSA clones p...

Rose, M.A., 1996: Effect of an AIDS education program for older adults. The purpose of this study was to examine the effect of an age-specific AIDS education program on HIV/AIDS knowledge, perceived susceptibility to AIDS, and perceived severity of AIDS in older adults. The health belief model served as a framework. T...

Rogers H.H.; Jeffries H.E.; Witherspoon A.M., 1979: Measuring air pollutant uptake by plants nitrogen di oxide. Direct kinetic determinations of the uptake of NO2 by selected plant species under various conditions were made using continuous stirred tank reactor (CSTR) techniques. Second-order rate constants with respect to exposure concentration and leaf ar...

Nebe, H.; Blume, N., 1971: Demonstration of antinuclear factors using indirect immunofluorescence in scleroderma patients. Dermatologische Monatschrift 157(1): 27-31

Bashir, R.; Al-Kawi, M.Z.; Harder, E.J.; Jinkins, J., 1985: Nervous system brucellosis: diagnosis and treatment. We treated six patients with nervous system brucellosis causing polyradiculitis (2 patients), myelopathy (2), encephalitis (1), or meningitis (1). Diagnosis was based on Brucella species cultured from one patient, and a twofold or greater rise in...

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D.S.ntis E.; Miceli C.; Porfiri B., 1984: Clinical pathologic and electron microscopic study of a case of adamantinoma of the tibia. Rivista di Anatomia Patologica e di Oncologia 43(1): 105-115