Insight into discovery of next generation reversible TMLR inhibitors targeting EGFR activating and drug resistant T790M mutants.

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Insight into discovery of next generation reversible TMLR inhibitors targeting EGFR activating and drug resistant T790M mutants.

Curr Cancer Drug Targets. 2017 Mar 30;:

Authors: Agarwal SM, Pal D, Gupta M, Saini R

Abstract
Cancer is one of the most challenging diseases among the various causes of deaths worldwide. Among cancer, lung cancer rules as the leading cause of cancer-related deaths annually.The majority of the lung cancers identified are non-small cell lung cancer (NSCLC). Clinically, the Epidermal Growth Factor Receptor (EGFR) is a therapeutically accepted target for NSCLC. Many therapeutic leads that target this transmembrane receptor protein were tested for anti-EGFR activity that led to the discovery of gefitinib and erlotinib. These ATP-competitive first generation EGFR inhibitors are the first-line treatment of EGFR-mutated lung cancer. Though, these have proven highly effective against EGFR activating mutants, but their inefficacy was noticed shortly after the treatment due to an acquired secondary mutation (T790M). Clinical studies demonstrated that this mutation alters the binding site which makes first generation inhibitors ineffective. Henceforth, second and third generation inhibitors emerged having covalent and irreversible mode of action. Second generation inhibitors like afatinib and dacomitinib exhibit inhibitory activity for both wtEGFR and EGFR T790M, while the third generation inhibitors like osimertinib and rociletinib inhibited only T790M resistance mutant, sparing the wild type. However, these were found toxic. This provided opportunity for exploration of novel molecules with a completely different mechanism of action. This review highlights the recent advances in the designing of non-covalent reversible next generation inhibitors and their future relevance in the treatment of NSCLC. The first aspect of this account deals with the reviews of research papers, identifying the key features of the synthesis and optimization strategies. The second aspect provides an analytical insight into the bonds and interactions, as well as major scaffolds utilized to synthesize newer molecules. Finally, applicability of next generation inhibitors over irreversible covalent inhibitors was explored in terms of potency and broad kinase selectivity. It is expected that this review will be useful for guiding medicinal chemists and structural biologists involved in the anticancer EGFR drug discovery.

PMID: 28359250 [PubMed - as supplied by publisher]

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