Targeting an EGFR Water Network with 4‐Anilinoquin(az)oline Inhibitors for Chordoma

Abstract

Quinoline‐ and quinazoline‐based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non‐small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N‐(3‐ethynylphenyl)‐6,7‐dimethoxyquinolin‐4‐amine], 4 [N‐(3‐ethynylphenyl)‐6,7‐dimethoxyquinazolin‐4‐amine], and 7 [4‐((3‐ethynylphenyl)amino)‐6,7‐dimethoxyquinoline‐3‐carbonitrile]. We also identified 6,7‐dimethoxy‐N‐(4‐((4‐methylbenzyl)oxy)phenyl)quinolin‐4‐amine (compound 18), which is the most potent inhibitor (IC50=310 nm) of the UCH‐2 chordoma cell line to date.

New Insights into 4-Anilinoquinazolines as Inhibitors of Cardiac Troponin I–Interacting Kinase (TNNi3K)

“…We have demonstrated a robust way to access the 4-anilinoquinazoline scaffold in good yield supported by previous literature [12][13][14][15][16][17][18][19]. We report the synthesis of several related 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNi3K).…”

“…The two other derivatives (2 and 20) were afforded by reaction of commercially available anilines 18 and 19, respectively, with 4-chloro-6,7-dimethoxyquinazoline (14a) via the same route as 7 and 15-17 to afford 2 in excellent yield (78%) and 20 in good yield (57%). Aniline 13 was then reacted with the corresponding 6-bromo-4-chloroquinoline derivatives (14a-d) to afford 4-anilinoquinazolines (7 and 15-17) via a nucleophilic aromatic substitution reaction in good overall yields (53%-67%) (Scheme 2) [12][13][14][15][16][17][18][19]. The two other derivatives (2 and 20) were afforded by reaction of commercially available anilines 18 and 19, respectively, with 4-chloro-6,7dimethoxyquinazoline (14a) via the same route as 7 and 15-17 to afford 2 in excellent yield (78%) and 20 in good yield (57%).…”

“…These tapes form two-dimensional, interleaved layers via π-π interactions parallel to the a-axis which close-pack to form the structure. Unit cell contents of 16H + Cl − , 17H + Cland 20H + Cl − shown in projection down the a-axis (16,17) or b-axis (20). Hydrogen bonds are shown as dashed green lines.…”

Design and analysis of the 4-anilino-quin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure activity relationships

“…GAK is known to be sensitive to aniline modifications particularly in the orthoand para-position. 38 We first selected 67, the 7-cyano quinazoline and installed several small halogens (87-90) on the aniline portion of the molecule. The three fluorine derivatives (87-89) showed a selectivity ratio improvement whereas the 4-chloro analog (91) did not.…”

“…All Compounds (1, 42, 48, 62, 71) 11 , (2, 10, 11) 12 , (3-8, 12-16, 20-22, 30, 40 38 were synthesised as previously reported. N-(3,4,5-trimethoxyphenyl) 13 3.70 (s, 3H).…”