探讨靶向EGFR激活和耐药T790M突变体的下一代可逆TMLR抑制剂的发现

Title:Insight into Discovery of Next Generation Reversible TMLR Inhibitors Targeting EGFR Activating and Drug Resistant T790M Mutants

Volume: 17 Issue: 7

关键词: EGFR，可逆抑制剂，共价抑制剂，激活突变，次级突变体，TMLR抑制剂

摘要: Background: Epidermal growth factor receptor (EGFR) is a well-recognised drug target exploited for treating non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first generation clinically employed inhibitors used against EGFR activating mutants. However, during course of treatment these inhibitors become ineffective due to the emergence of an acquired secondary mutation. Subsequently, in order to overcome non-responsiveness second and third generation inhibitors were designed having covalent bond and irreversible mode of action. However, these inhibitors were shown to be toxic. This led to the discovery of lead candidates with completely different mode of action and therapeutic efficacy.

Objective: We have reviewed the recent efforts undertaken by researchers in discovering newer noncovalent reversible next generation inhibitors for treating NSCLC.

Methods: We first studied the optimization steps and pharmacokinetic variables of the synthesised molecules. We also analysed bonds and interactions using PDB X-ray crystal structures as well as scaffold and selectivity analysis was undertaken.

Results: We identified that ligand lipophilic efficiency driven potency is a preferable optimisation parameter for maintaining drug likeliness of the molecule. Also, few h-bonds were recognised as major players in affecting the binding of compound. The scaffold analysis revealed that ligand molecules with pyrimidine core exhibit higher inhibitory activity against TMLR, as well as higher selectivity with respect to other kinases.

Conclusion: Next generation reversible inhibitors exhibited unique binding mode and were found to occupy three major pockets (ribose pocket, back pocket and hinge region), which is critical for increasing the selectivity of the compound against TMLR mutants.

Cite this article as:

Insight into Discovery of Next Generation Reversible TMLR Inhibitors Targeting EGFR Activating and Drug Resistant T790M Mutants, Current Cancer Drug Targets 2017; 17 (7) . https://dx.doi.org/10.2174/1568009617666170330112842

DOI https://dx.doi.org/10.2174/1568009617666170330112842	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576