Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors

Abstract

The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL kinase. Through optimization and detailed SAR studies we developed low nanomolar inhibitors, and after further biological characterization we identified a potent AXL kinase inhibitor with favorable pharmacokinetic profile. The antitumor activity was determined in xenograft models, and the lead compounds reduced the tumor size by 40% with no observed toxicity as well as lung metastasis formation by 66% when compared to vehicle control.

Discovery of Potent Plasmodium falciparum Protein Kinase 6 (PfPK6) Inhibitors with a Type II Inhibitor Pharmacophore

“…Considering that known targets of Ki8751 are in the TK group and Aurora family of kinases [24][25][26][27] , it was especially intriguing to find Ki8751 as a hit against PfPK6, a member of the CMGC group. To investigate the kinome-wide inhibitory potential of this scaffold, we screened Ki8751 against 97 human kinases using a thermal shift assay (Figure S1 and Table S2).…”

“…We thus aim to investigate other heterocycles, maintaining the relative position of the N1 atom of the quinoline ring in Ki8751. Isosteric replacements of the quinoline with thieno [3,2-b]pyridine (25) was tolerated by PfPK6, but the thieno [2,3-b]pyridine isomer (27) was less preferred. We hypothesized that the efficiency of the annulated ring may be enhanced by the formation of an additional hydrogen bond with the carbonyl group of the outer hinge residue of the kinase (hinge.48, based on numbering in KLIFS 31 ).…”

Asymmetric Synthesis of 2,2‐Difluorotetrahydrofurans through Palladium‐Catalyzed Formal [3+2] Cycloaddition

“…Product 3 a was easily oxidized to aldehyde, [10] which was then further transformed to quinoline 6 promoted by a Pd/C-catalyzed hydrogenation. [11] On the other hand, the two diastereomers underwent the hydroboration-oxidation, [12] followed by oxidation, [13] reduction, [14] and condensation reactions to afford the corresponding seven-membered cyclic amides. The enantioselectivity of all products can be maintained and the absolute configurations of (3aS,9bS)-6 and (3aR,10bR)-8 were determined by X-ray crystallography.…”

New N-(3′-acetyl-8-nitro-2,3-dihydro-1H,3′H-spiro[quinoline-4,2′-[1,3,4]thiadiazol]-5′-yl) acetamides induced cell death in MCF-7 cells via G2/M phase cell cycle arrest

“…Quinoline heterocycles are a significant class of compounds that are found in several natural products and synthetic scaffolds. The early reports discovered that quinoline analogues inhibit the growth of cancer cells by targeted mechanisms of action such as estrogen receptor binding, 13 an estrogen receptor degrader, 14 topoisomerase 1 (Top1) inhibitors, 15 inhibition of histone deacetylase 6, 16 inhibition of c-KIT kinase, 17 ataxia telangiectasia mutated (ATM) kinase inhibition, 18 topoisomerase IIα (TOP2A) inhibition, 19 HSP90 inhibitors, 20 dihydroorotate dehydrogenase (hDHODH) inhibitors, 21 inhibition of AXL kinase, 22 inhibition of mutant isocitrate dehydrogenase 1 (mIDH1), 23 inhibition of Rho-associated protein kinase (ROCK), 24 and inhibition of aldehyde dehydrogenase 1A1 (ALDH1A1). 25 Because of these crucial activities of quinoline scaffolds, recently we have reported 8-nitroquinolone based compounds, which displayed good antitumor properties.…”