TOK001 is an experimental drug being developed by Tokai Pharmaceuticals

by Selleckchem | Jul 16 2013

The ErbB proteins are a four-member family of highly homologous receptor tyrosine kinases comprised of ErbB1 , ErbB2 , ErbB3 , and ErbB4 . These proteins consist of a ligand-binding extracellular domain , a transmembrane domain, an intracellular tyrosine kinase domain, and a c-terminal signaling tail. An intracellular signal is generated through receptor dimerization and transphosphorylation TOK-001 of their c-terminal tails . The differentiation of this family from a primordial ErbB gene has been associated with functional complimentarity and a necessity for cooperative activity in some of its members. Such cooperativity is exemplified by HER2 and HER3. HER2 has evolved into a catalytic driver, with robust kinase activity but no ligand-binding ability and little ability for self-regulation. On the other hand, HER3 has no significant kinase activity but is an optimal dimerization and regulatory partner for HER2 . In fact, in the presence of ligand stimulation, the HER2-HER3 heterodimer is the most active signaling unit in this family . EGFR, on the other hand, has Raf maintained its bifunctional attributes and performs equally well as a catalytic or ligandactivated NVP-BGJ398 regulatory partner . The reduced ability of HER2 to self-regulate suggests a potent oncogenic potential, and indeed overexpression of HER2 is seen in a number of human cancers, mostly breast cancers. The etiologic role of HER2 in tumorigenesis has been extensively studied in mouse transgenic models, confirming unequivocally the potent tranforming potential of the mouse HER2 homolog Neu when overexpressed or overactive . The driving role of HER2 in tumorigenesis and KRP-203 the large number of cancer patients affected by this cancer subtype have made HER2 a high priority target for drug development for the past two decades. Initial attempts to target HER2 in the 1980s focused on the development of monoclonal antibodies to interfere with functions residing within its ECD. These efforts have produced clinically active drugs, but they do not appear to effectively inactivate HER2 signaling and the molecular basis for their clinical activities remains undefined . Furthermore, the HER2 ECD is redundant for its oncogenic function and is often proteolytically cleaved in tumors, indicating a potential limitation of ECD-targeting approaches . However, the HER2 TK domain is essential for its transforming function and targeting the catalytic TK function of HER2 presents the most compelling approach EMD1214063 for the development of highly effective anti-cancer drugs. Numerous HER-family selective TK inhibitors have been synthesized over the past decade and are listed in Table 1. The ongoing evolution of these TKIs started with investigations of EGFR, followed by pan-HER family inhibitors, followed only recently by HER-2 selective compounds. There is still much to be learned about the structure-activity relationships for these new HER-2 selective drugs. This review focuses on the key structural classes and discovery strategies for the HER family kinase inhibitors; a detailed analysis of preclinical models or clinical activity is outside the current scope. For clinical evaluation, the reader is directed to the references in Table 1 and to other recent reviews .