Elsevier

Pharmacological Research

Volume 87, September 2014, Pages 42-59
Pharmacological Research

Invited Review
ErbB/HER protein-tyrosine kinases: Structures and small molecule inhibitors

https://doi.org/10.1016/j.phrs.2014.06.001Get rights and content

Abstract

The epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1–4). These receptors consist of an extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. The ErbB proteins function as homo and heterodimers. Growth factor binding to EGFR induces a large conformational change in the extracellular domain. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric dimer. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas. Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer and lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Moreover, monoclonal antibodies that target the extracellular domain of ErbB2 are used for the treatment of ErbB2-positive breast cancer and monoclonal antibodies that target ErbB1 and are used for the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them, and a current goal of research is to develop drugs that are effective against drug-resistant tumors.

Section snippets

Biology of the ErbB/HER family of receptors

The ErbB/HER receptor protein-tyrosine kinases are ubiquitously expressed in epithelial, mesenchymal, cardiac, and neuronal cells and in their cellular progenitors [1]. This group of receptors, which includes the epidermal growth factor receptor (EGFR), is among the most studied cell signaling families in biology. They regulate apoptosis, cell cycle progression, differentiation, development, and transcription. EGFR was the first receptor to be characterized as a protein-tyrosine kinase, which

Receptor homo and heterodimers

Ullrich et al. were the first to determine the amino acid sequence of a receptor protein-tyrosine kinase (EGFR) using cDNA sequence analysis [10]. They hypothesized that the receptor consisted of an extracellular domain, a single hydrophobic transmembrane segment, and an intracellular domain with protein kinase activity. This hypothesis has stood the test of time and fundamentally applies to all receptor protein kinases. The ErbB family of protein kinases consists of a glycosylated

Properties of the small and large lobes

The ErbB/HER protein kinase domains have a small amino-terminal lobe and large carboxyterminal lobe first described by Knighton et al. for PKA (Fig. 3) [28]. The two lobes form a cleft that serves as a docking site for ATP. The small lobe contains a conserved glycine-rich (GxGxxG) ATP-phosphate-binding loop, sometimes called the P-loop, which is the most flexible part of the small lobe. This loop is near the phosphates of the ATP substrate. The β1 and β2-strands of the N-lobe harbor the adenine

Binding pocket for ATP and small molecule inhibitors

The glycine-rich loop, or P-loop, occurs universally in protein kinases and consists of a canonical GxGxxΦG sequence where Φ refers to a hydrophobic residue. This sequence in the ErbB family is composed of GSGAFG (Table 2). The P-loop, which forms a lid above the ATP phosphates, is characteristically one of the most mobile portions of the protein kinase domain. This mobility may be due to the requirement that the enzyme binds ATP and then releases ADP following catalysis. In PKA, the second

Phosphoryl transfer transition states

The catalytic mechanisms of protein kinases have been addressed by steady-state and transient kinetics, site specific mutations, quantum mechanical and molecular mechanics simulations, X-ray crystallography, and NMR spectroscopy. Most studies have been performed with PKA, and there is a general consensus that these fundamentals will hold for other protein kinases. However, each class of protein kinase is expected to exhibit its unique variations from the reaction template. The transfer of the

Mutant ERBB1 oncogenic activation

ErbB1/EGFR plays an important role in the pathogenesis of many lung cancers. Herbst et al. reported that EGFR kinase-domain mutations occur in a range of 10–40% of lung cancer samples [75]. The incidence of EGFR kinase-domain mutations is about 10% in Caucasian populations and 30–40% in Asian patients. About 10% of unselected patients with NSCLC exhibited rapid and often dramatic responses to gefitinib [76]. In 2004, three groups compared the tumors of patients who responded to gefitinib with

Epilog

The ErbB family of receptor protein-tyrosine kinases participates in the pathogenesis of several common malignancies listed in Section 1.2. Several small molecule ErbB kinase domain inhibitors have been approved by the FDA for the treatment of lung cancer (afatinib, erlotinib, and lapatinib) and breast cancer (lapatinib). Furthermore several biopharmaceutical agents have been approved for the treatment of breast (pertuzumab, trastuzumab, and ado-trastuzumab emtansine) and colorectal cancer

Conflict of interest

The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review.

Acknowledgments

The author thanks Prof. John Kuriyan for providing the protein data bank file for the EGFR asymmetric dimer. He also thanks Laura M. Roskoski for providing editorial and bibliographic assistance.

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