Challenges and Perspectives on the Development of Small-Molecule EGFR Inhibitors against T790M-Mediated Resistance in Non-Small-Cell Lung Cancer

Abstract

Because of the development of drug-resistance mutations, particularly the "gatekeeper" threonine(790)-to-methionine(790) (T790M) mutation in the ATP-binding pocket of the epidermal growth factor receptor (EGFR), the current generation of EGFR tyrosine kinase inhibitors lost their clinical efficacy. Recently, a large number of small-molecule inhibitors with striking inhibitory potency against EGFR mutants with the T790M change have been identified. In particular, the inhibitors rociletinib and osimertinib, which can selectively target both sensitizing mutations and the T790M resistance while sparing the wild-type (WT) form of the receptor, have been designated as breakthrough therapies in the treatment of mutant non-small-cell lung cancer (NSCLC) by the U.S. FDA in 2014. We hope that this review on the small-molecule EGFR T790M inhibitors, along with their discovery strategies, will assist in the design of future T790M-containing EGFR inhibitors with high levels of selectivity over WT EGFR, broad kinase selectivity, and desirable physicochemical properties.

Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

“…Unfortunately, only osimertinib possesses exceptional biological properties, and has thus been approved in 2015 for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC [16]. On the basis of considerable efforts to identify more effective and safe agents to overcome gefitinib-produced resistances [17][18][19], we found the novel diphenylpyrimidine derivative N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (6, DY3002, Figure 2) [20]. The molecule displayed enhanced activity and increased selectivity against EGFR T790M and was thus reported as a promising NSCLC clinical candidate.…”

Targeting EGFRL858R/T790M and EGFRL858R/T790M/C797S resistance mutations in NSCLC: Current developments in medicinal chemistry

“…As collected from Thomson Reuters Cortellis recently, there are many types of covalent selective EGFR‐TKIs that have been developed to overcome the EGFR T790M clinical resistance mutation (Table ). These inhibitors have good selectivity for the double mutant over WT EGFR, thus overcoming the clinical toxicity seen with the second‐generation EGFR‐TKIs . Almost all of these inhibitors adopt a U‐shaped conformation in the EGFR T790M active site to present an acrylamide group to Cys797 and selectively form a covalent complex.…”

“…These inhibitors have good selectivity for the double mutant over WT EGFR, thus overcoming the clinical toxicity seen with the second-generation EGFR-TKIs. 60,61 Almost all of these inhibitors adopt a U-shaped conformation in the EGFR T790M active site to present an acrylamide group to Cys797 and selectively form a covalent complex.…”

Structural optimization of diphenylpyrimidine scaffold as potent and selective epidermal growth factor receptor inhibitors against L858R/T790M resistance mutation in nonsmall cell lung cancer

“…For example, Compound 11 is a typical JNK3 inhibitor, compound 12 is a EGFR inhibitor, and compound 13 is Bcl‐2 inhibitor (Figure ). Based on the novel pyrimidine biological template, we synthesized a new class of thiopyrimidine derivatives to improve the activity and selectivity against EGFR T790M enzyme (Figure ). Moreover, their activity against wild‐type EGFR and EGFR T790M‐mutated enzymes, as well as their activity against NSCLC cell lines were also described in this manuscript.…”