Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

Abstract

The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand-protein interactions of the reviewed molecules are summarized.

Keywords: SAR studies; antiproliferative compounds; biological data; carcinogenic pathways; kinases modulators; quinoline; targeted therapy.

Figure 1

(a) Quinoline 1 or 1-aza-naphthalene and benzo[b]pyridine; (b) quinoline 3D structure; (c) quinoline electron density; (d) electron density encoded with the electrostatic potential.

Figure 2

Cross-talk between EGFR, VEGFR, and c-Met signalling pathways; in boxes are reported some quinoline based inhibitors developed up to date.

Figure 3

C-Met quinoline inhibitors: cabozantinib and foretinib (in boxes structure analogies are highlighted).

Figure 4

(a) crystal structure of kinase domain of c-Met in complex with foretinib (PDB ID: 3LQ8). In the box the binding cavity of the receptor occupied by the quinoline small molecule is illustrated (the activation loop is represented with transparent surface) [31]; (b) interactions of foretinib with amino acid residues of the c-Met active site [32].

Figure 5

General structure for quinoline c-Met inhibitors as analogues of cabozantinib and foretinib.

Figure 6

Binding models with c-Met kinase domain of quinoline- based compounds (a) 3 [35]; (b) 4 [36]; (c) 7 [38]; (d) 9 [40]; (e) 10 [41]; (f) 16 [48]; (g) 19 [51].

Figure 7

(a) structures of a new cluster of 3,5,7-trisubstituted quinoline compounds with promising anticancer activity on c-Met [55,57]; (b) crystal structure of zgwatinib in complex with the kinase domain of c-Met (residues coloured in cyan form hydrophobic interactions with the ligand, whereas those coloured in yellow formed H-bonds, indicated with black dash lines; PDB id: 4GG5), [56].

Figure 8

4,6,7-substitued quinoline derivatives selectively active on c-Met [58,59].

Figure 9

Main interactions of compound 28 with the amino acid residues in c-Met active site [59].

Figure 10

Structures of some hybrid quinoline derivatives as c-Met inhibitors.

Figure 11

Crystal structure of omipalisib in complex with the catalytic subunit of PI3Kγ (PDB id: 3L08) and detailed interactions [67,73].

Figure 12

The most active derivative of 3-phenylsulfonylurea-4-aniline quinoline series [76].

Figure 13

Imidazo[4,5-c]quinoline derivatives as promising anticancer PI3K/mTOR inhibitors.

Figure 14

Model for the interactions of dactolisib in the ATP-binding cleft of PI3Kα [78,84].

Figure 15

Thieno[3,2-c]quinoline compound active as PI3K inhibitor [104].

Figure 16

(a) mTOR inhibitors containing pyrazino[2,3-c]quinolin-2(1H)-one scaffold; (b) structures of torin 1 and torin 2, mTOR inhibitors containing benzo[h]-1,6-naphthyridin-2(1H)-one scaffold [105,106,107].

Figure 17

4-anilinoquinoline-3-carbonitrile 44 and of the approved 4-anilinoquinazoline EGFR inhibitors gefitinib, erlotinib, afatinib.

Figure 18

Structures of the irreversible EGFR inhibitors pelitinib (EKB-569), neratinib (HKI-272), and pyrotinib (SHR-1258).

Figure 19

EGFR/T290M mutant kinase domain (PDB id: 2JIV) in complex with neratinib [113].

Figure 20

(a) binding mode of pyrotinib in the catalytic region of HER2 kinase; (b) overlap binding mode of neratinib (colored blue) and pyrotinib (colored yellow) [114].

Figure 21

Structure of 4-(2-aryl-cyclopropylamino)-quinoline-3-carbonitrile as selective inhibitor of EGFR [118].

Figure 22

4-anilino-3-carboxyamide derivatives as EGFR inhibitors [119,120].

Figure 23

2-styrylquinolines 48 and 49 as promising EGFR inhibitors [121].

Figure 24

Schiff’s base quinoline derivative as EGFR tyrosine kinase inhibitor [122].

Figure 25

Pyrazoline/pirazolinylthiazole quinoline hybrids [123].

Figure 26

(a) Thieno[2,3-b]quinoline-2-carboxamide-chalcone derivative 54; (b) orientation and interactions of 54 within the EGFR active site [124].

Figure 27

Structure of benzo[h]quinoline derivative [125].

Figure 28

Structures of VEGFR inhibitors with quinoline-urea moiety lenvatinib, Ki8751, tivozanib.

Figure 29

(a) crystal structure of lenvatinib in complex with VEGFR-2 (PDB id: 3WZD); (b) binding pocket of VEGFR-2 occupied by lenvatinib; (c) scheme for interactions of lenvatinib in the VEGFR-2 binding pocket [130].

Figure 30

Structure of the quinoline VEGFR-2 inhibitor 56 [133].

Figure 31

Structure of compound 57, a 7-Chloro-4-(piperazin-1-yl)quinoline derivative with VEGFR-2 inhibition activity [134].

Figure 32

Quinoline-3-carboxylic acid derivatives with VEGFR-2 and VEGFR-3 inhibition activity [135].

Figure 33

Structure of 3-aryl-quinoline derivatives 60 and 61, dual VEGFR-2/ERα inhibitors [136].

Figure 34

Quinoline-based molecules with inhibition activity on Ras.

Figure 35

(a) Structures of diarylurea derivative sorafenib and of quinoline inhibitors 64,65 as selective inhibitors of Raf.; (b) The best docked pose of 64 within the C-Raf active site (two H-bond stabilize the ligand-protein complex: amidic carbonyl oxygen-Thr⁴²¹, quinolinyl nitrogen-Asn⁴⁷²); (c) best docked pose for 65 in C-Raf active site (three H-bond stabilize the interaction: urea carbonyl oxygen-catalytic Lys⁴⁷⁰, urea terminal nitrogen-Asp⁴⁸⁶, quinolinyl nitrogen-Lys⁴³¹) [139,140].

Figure 36

(a) Quinoline inhibitors of Raf compared with the reference compound sorafenib; (b) overlay of the docked pose of compound 67 (magenta) and co-crystalized sorafenib (black) in the catalytic kinase domain of BRAF^V600E (PDB id: 1UVJ); (c) superimposition of the docked pose of compound 67 (magenta) and 66 (orange) in the catalytic kinase domain of BRAF^V600E (PDB id: 1UVJ) [141,142].

Figure 37

3,3-dimethyl-1H-pyrrolo[3,2-g]quinolin-2(3H)-one derivative as potent C-Raf inhibitor [143].

Figure 38

Structures of some MEK inhibitors with 4-anilino-quinoline-3-carbonitrile core [144,145,146,147].

Figure 39

Structure of MEK inhibitor 1H-imidazo[4,5-c]quinoline 75.

Figure 40

(a) structure of the quinoline derivative of ursolic acid 76; (b) binding pose of 76 within MEK1 kinase domain (PDB id: 3EQF); (c) ligand interactions of 76 docked into MEK1 active site [149].