Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors.

Feifei Fang; Yang Dai; Hao Wang; Yinchun JI; Xuewu Liang; Xia Peng; Jiyuan LI; Yangrong Zhao; Chunpu LI; Danyi Wang; Yazhou LI; Dong Zhang; Dan Zhang; Meiyu Geng; Hong Liu; Jing AI; Yu Zhou

Return

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors.

Author: Feifei FANG ¹ ; Yang DAI ² ; Hao WANG ³ ; Yinchun JI ² ; Xuewu LIANG ² ; Xia PENG ² ; Jiyuan LI ² ; Yangrong ZHAO ² ; Chunpu LI ² ; Danyi WANG ² ; Yazhou LI ² ; Dong ZHANG ² ; Dan ZHANG ² ; Meiyu GENG ² ; Hong LIU ² ; Jing AI ² ; Yu ZHOU ³
Author Information

1. Lingang Laboratory, Shanghai 200031, China.
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3. Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Publication Type:Journal Article
Keywords: Antitumor activity; Antitumor drug development; Fused-pyrazolone carboxamide derivatives; Potential AXL inhibitor; Structure-based drug design
From: Acta Pharmaceutica Sinica B 2023;13(12):4918-4933
CountryChina
Language:English
Abstract: As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC₅₀: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC₅₀: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.