Role of neurotrophin-trk interactions in oncology: the anti-tumor efficacy of potent and selective trk tyrosine kinase inhibitors in pre-clinical tumor models.
The increasing knowledge of the pathogenic mechanisms involved in cancer cell growth has enabled the implementation of mechanism based drug design approaches rather than the more conventional nonspecific approaches. Drugs that interfere with cellular signal transduction pathways are currently a major focus in development of newer therapeutic technologies in oncology. The therapeutic utility of potent and selective tyrosine kinase inhibitors in oncologic applications has become widely recognized for several years, however targeting neurotrophin receptors as a molecular target driven approach has only recently been realized. This review presents the hypothesis of the neurotrophin-trk receptors as a viable molecular target for medicinal chemical intervention in tumor biology, followed by an overview of the pre-clinical studies which culminated in the advancement of the first potent trk tyrosine kinase inhibitor CEP-2563 (KT-8391), and the orally active K-252a analog, CEP-701 (KT-5555) into clinical evaluation.
Ruggeri
B A
BA
Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. bruggeri@cephalon.com
Miknyoczki
S J
SJ
Singh
J
J
Hudkins
R L
RL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000592:standards*; D002227:Carbazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D005663:Furans; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles; D051379:Mice; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D026121:Indole Alkaloids; D007211:Indoles; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C049985:staurosporine aglycone; C119379:lestaurtinib; D011505:Protein-Tyrosine Kinases