A Chemical Tuned Strategy to Develop Novel Irreversible EGFR-TK Inhibitors with Improved Safety and Pharmacokinetic Profiles

Abstract

Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFR(WT), EGFR(T790M) as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFR(L858R/T790M) driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.

Covalent EGFR Inhibitors: Binding Mechanisms, Synthetic Approaches, and Clinical Profiles

“…Attenuated electrophiles have a diminished probability of irreversible interaction with off‐target proteins . This strategy was adopted to enhance the safety and pharmacokinetic properties of quinazoline‐based irreversible EGFR inhibitors where fluorosubstituted olefins ( 80 , 81 ) can be tuned to alter Michael addition reactivity . Also, incorporation of fluorine into small molecules has been previously employed to optimize drug‐like properties, such as changes in cell uptake, tissue distribution, metabolic stability, and improved pharmacokinetic properties .…”

“…Also, the concentration in the brain is higher than that of afatinib ( 16 ). This indicates that fluoro substitution enhances brain uptake; therefore, quinazoline analogs bearing fluorosubstituted olefins ( 80 , 81 ) can be considered as candidates for the treatment of NSCLC patients with brain metastasis .…”

Zielgerichtete kovalente Inhibitoren für das Wirkstoffdesign

“…Dieser neue Ansatz, der zur Entdeckung wirksamer, selektiver, reversibler kovalenter Inhibitoren der p90‐ribosomalen Protein‐S6‐Kinase RSK2 führte (Abbildung ), verbindet die Vorteile von reversiblen und irreversiblen TCI‐Mechanismen derart, dass die Proteinstilllegung bestehen bleibt, bis die Kinase abgebaut wird, und erst zu diesem Zeitpunkt der Ligand abdissoziiert, der nun keine kovalent modifizierten Peptidfragmente hinterlässt, die vom Immunsystem als “fremd” erkannt werden . Vor kurzem wurde dieses Konzept des “chemisch abgestimmten Elektrophils” auf das Design kovalenter Inhibitoren für Wirkstoff‐resistente Formen von EGFR ausgedehnt, und es gibt Hinweise, dass das günstige Sicherheitsprofil des reaktiven α‐Cyan‐α,β‐ungesättigten Ketons Bardoxolon‐Methyl (CDDO‐Me) aus der Bildung eines transienten kovalenten Addukts mit dem Thiol‐reichen elektrophilen Sensorprotein Keap1 resultiert…”

Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

“…[6][7][8][9] CI-1033 (canertinib) 10 , HKI-272 (neratinib) 11,12 and PF-00299804 (dacomitinib) 13 advanced into late stage clinical development and structurally resemble the first generation of EGFR inhibi-tors ( Figure 1). Afatinib (gilotrif) was recently approved by the US FDA for treatment of late-stage NSCLC patients with actively mutated EGFR.…”