Transforming the TGFbeta pathway: convergence of distinct lead generation strategies on a novel kinase pharmacophore for TbetaRI (ALK5).
The pathological activation of the transforming growth factor beta (TGFbeta) pathway plays a critical role in the progression of fibrotic diseases and also enhances tumor invasiveness and metastasis. Due to its central role in TGFbeta signaling, the TGFbeta type I receptor (TbetaRI) is emerging as an exciting target for blockade of the TGFbeta pathway. In this review we will discuss how three independent drug discovery strategies, ie, target-hopping, high-throughput screening and virtual screening, have converged in the identification of inhibitors of TalphaRI kinase. Structural studies have provided insight into the potency and selectivity of these inhibitors and form the basis for structure-based design optimization strategies. These efforts have enabled the production of potent, selective inhibitors for dissecting the TGFalpha pathway and assessing the usefulness of TalphaRI blockade in the treatment of fibrotic diseases and cancer.
Singh
Juswinder
J
Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA. Juswinder.Singh@biogenidec.com
Ling
Leona E
LE
Sawyer
J Scott
JS
Lee
Wen-Cherng
WC
Zhang
Faming
F
Yingling
Jonathan M
JM
D030201:Activin Receptors, Type I / Q000494:pharmacology / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D015394:Molecular Structure; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use
D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human