Allosteric therapies for lung cancer

Abstract

Allostery is a regulation at a distance by conveying information from one site to another and an intrinsic property of dynamic proteins. Allostery plays an essential role in receptor trafficking, signal transmission, controlled catalysis, gene turn on/off, or cell apoptosis. Allosteric mutations are considered as one of causes responsible for cancer development, leading to "allosteric diseases" by stabilizing an active or inactive conformation or changing the dynamic distribution of preexisting propagation pathways. The present article mainly focuses on the potential of allosteric therapies for lung cancer. Allosteric drugs may have several advantages over traditional drugs. The epidermal growth factor receptor mutations and signaling pathways downstream (such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways) were suggested to play a key role in lung cancer and considered as targets of allosteric therapy. Some allosteric inhibitors for lung cancer-specific targets and a series of preclinical trials of allosteric inhibitors for lung cancer have been developed and reported. We expect that allosteric therapies will gain more attentions to develop combinatorial strategies for lung cancer and metastasis.

Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors

“…There have been recent developments in compounds targeting the allosteric site in order to produce an alternative medicine that might solve the resistance issue to drugs used in current therapy [ 101 ]. Furthermore, the ligands binding to this site, which are also called allosteric modulators of EGFR, lead to conformational changes that may enhance the protein activity and orthosteric ligand binding, or vice versa [ 102 , 103 , 104 ]. They are divided into three types based on their properties, namely positive (PAM), neutral, and negative allosteric modulators (NAM) [ 103 , 105 ].…”

Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

“…This region is not directly involved with the pharmacotherapeutic response. The binding of effector to the allosteric site on the protein leads to conformational changes at the active or binding site, which regulates protein activity [42]. Allosteric ligands/effectors or drugs are of two types (1) non-covalent and (2) covalent binding agents.…”

“…EAI001 has only one chain (A) of which 28% is composed of the helix, and 14% is the β-plated sheet, which comprises 355 amino acids ranging from residue 675 to 1022 [47]. EAI001 has one inhibitory residue, namely 9LLA 1101 [42]. The figure states the residue sequence of both the compound along with this interaction site with the protein in the allosteric site of EGFR.…”