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.