Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor

Abstract

Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del T790M/L858R, and T790M/del) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.

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

“…In order to improve the activity against the activating single and double mutants of EGFR, the substituted piperidine was replaced by an N-alkylsulfonylpyrazole, leading to one of the most potent compounds 26f. 15 Compound 26f exhibited comparable activity against the EGFR T790M/L858R and EGFR T790M/del (746-750) mutants and improved activity against the L858R and del (746-750) single mutants, while also showing improved activity against EGFR WT . The X-ray complex of compound 26f and EGFR T790M/L858R suggested that the hydrogen bonds between the sulfonylpyrazole group and Lys745, and the hydrophobic interactions formed between the cyclopropyl group and Phe723 were responsible for the increased activity relative to the piperidinecontaining series ( Figure 20B).…”

“…One of the most potent compounds, 26e (Figure ), bearing a cis ‐fluorohydroxypiperidine, a hydroxyethyl group, and a trifluoropropyl group displayed surprising potency against EGFR T790M/L858R and EGFR T790M/del (746‐750) , with 125‐fold selectivity over EGFR WT and promising efficacy in a xenograft model. In order to improve the activity against the activating single and double mutants of EGFR, the substituted piperidine was replaced by an N ‐alkylsulfonylpyrazole, leading to one of the most potent compounds 26f . Compound 26f exhibited comparable activity against the EGFR T790M/L858R and EGFR T790M/del (746‐750) mutants and improved activity against the L858R and del (746‐750) single mutants, while also showing improved activity against EGFR WT .…”

“…Another T790M‐selective EGFR‐TKI HM61713 (olmutinib) was first launched in Korea in 2016 for the treatment of patients with locally advanced or metastatic EGFR T790M ‐positive NSCLC. In addition, several reversible inhibitors of EGFR L858R/T790M, such as those based on an aminopyrimidine scaffold, have also been reported as having good mutant‐EGFR potency and selectivity without utilizing covalent interaction with Cys797. However, several studies have now revealed that a tertiary C797S point mutation is the leading mechanism of resistance to the third‐generation mutant‐selective irreversible EGFR‐TKIs .…”

“…) with distinct chemical scaffolds, such as pyrimidine[4,5-d]pyrimidin-4(1H)-one(15) 80 and pyrido[2,3-d]pyrimidine-7-one derivatives (16 and 17).81 One of the most potent compound 15 bound to EGFR L858R/T790M with a K d value of 2.6 nM being 119-fold greater than the K d value with EGFR WT . Compound 15 displayed highly potent and specific EGFR T790M biochemical inhibition (EGFR L858R/T790M IC 50 = 2.18 nM) and strongly suppressed the proliferation of EGFR T790M -mutated H1975 NSCLC cells with an IC 50 value of 86 nM, while being less potent against NSCLC cells with EGFR WT .…”

Molecular Dynamic Simulations and Binding Free Energy Evaluations of Thiazolo-[2,3-b] Quinazolinone Derivatives With wtEGFR-TKD and "TMLR" Mutant EGFR-TKD

“…Exon 18 and 20 mutations result loss of P772, H773, and the addition of P, C, and Q amino acids, respectively [8][9][10] . The double mutations occurred in EGFR-TKD by T790M/L858R (TMLR) and T790M/del 746−750 (TMdel) is also known as point mutation 11,12 .…”