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

doi:10.1016/j.apsb.2023.10.002

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

Acta Pharm Sin B. 2023 Dec;13(12):4918-4933. doi: 10.1016/j.apsb.2023.10.002. Epub 2023 Oct 10.

Authors

Feifei Fang¹, Yang Dai², Hao Wang^{3

4}, Yinchun Ji², Xuewu Liang^{2

4}, Xia Peng², Jiyuan Li², Yangrong Zhao², Chunpu Li^{2

4}, Danyi Wang^{2

4}, Yazhou Li², Dong Zhang², Dan Zhang², Meiyu Geng^{2

4

5

6}, Hong Liu^{2

4

6}, Jing Ai^{2

4

6}, Yu Zhou^{3

4

6}

Affiliations

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.
⁴ University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
⁶ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.

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.

Keywords: Antitumor activity; Antitumor drug development; Fused-pyrazolone carboxamide derivatives; Potential AXL inhibitor; Structure-based drug design.