Small molecule inhibitors of Lck: the search for specificity within a kinase family.
The Src family of non-transmembrane protein kinases is comprised of eleven homologous members in mammals. Together, these kinases regulate a wide variety of cellular processes including cell survival, proliferation, differentiation, and motility. One member of this family, Lck, plays a pivotal role in T-cell signaling. Inhibition of Lck with small molecules has significant potential for therapeutic immunosuppression and treatment of diseases such as rheumatoid arthritis and asthma. Critical for successful clinical use of any Lck inhibitor is high specificity for Lck as inhibition of other members of the Src kinase family may result in unwanted side effects. In this review we provide an overview of the various synthetic compounds currently under investigation as Lck-specific inhibitors. In addition we provide an analysis of the properties of these compounds that account for the specificity required for the inhibition of one of eleven highly similar kinases.
Meyn
Malcolm A
MA
University of Pittsburgh School of Medicine, Department of Molecular Genetics and Biochemistry, 200 Lothrop St., Pittsburgh, PA 15213-2536, USA.
Smithgall
Thomas E
TE
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013379:Substrate Specificity; D013844:Thiazoles / Q000494:pharmacology*
C505452:1-methyl-1H-indole-2-carboxylic acid (4-(1-(4-(4-acetylpiperazin-1-yl)cyclohexyl)-4-amino-1H-pyrazolo(3,4-d)pyrimidin-3-yl)-2-methoxyphenyl)amide; C481959:BMS-243117; D011720:Pyrazoles; D011743:Pyrimidines; D013844:Thiazoles; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)