Discovery of novel Bcr-AblT315I inhibitors with flexible linker. Part 1: Confirmation optimization of phenyl-1H-indazol-3-amine as hinge binding moiety

Xiaoyan Pan; Liyuan Liang; Ying Sun; Ru Si; Qingqing Zhang; Jin Wang; Jia Fu; Junjie Zhang; Jie Zhang

doi:10.1016/j.ejmech.2019.05.091

Discovery of novel Bcr-Abl^T315I inhibitors with flexible linker. Part 1: Confirmation optimization of phenyl-1H-indazol-3-amine as hinge binding moiety

Eur J Med Chem. 2019 Sep 15:178:232-242. doi: 10.1016/j.ejmech.2019.05.091. Epub 2019 Jun 3.

Authors

Xiaoyan Pan¹, Liyuan Liang¹, Ying Sun¹, Ru Si¹, Qingqing Zhang¹, Jin Wang¹, Jia Fu¹, Junjie Zhang², Jie Zhang³

Affiliations

¹ School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
² School of Science, Xi'an Jiaotong University, Xi'an, 710049, China.
³ School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China. Electronic address: [email protected].

PMID: 31185413
DOI: 10.1016/j.ejmech.2019.05.091

Abstract

As a continuation to our research, a series of novel Bcr-Abl inhibitors incorporated with 6-phenyl-1H-indazol-3-amine as hinge binding moiety (HBM) were developed based on confirmation analysis. Biological results indicated that these compounds exhibited an enhanced inhibition against Bcr-Abl^WT and Bcr-Abl^T315I in kinases assays, along with improved anti-proliferative activities in K562 cell assays. In particular, compound Y9 displayed comparable potency with that of imatinib. It potently inhibited Bcr-Abl^WT and Bcr-Abl^T315I kinases with IC₅₀ of 0.043 μM and 0.17 μM, respectively. Furthermore, compound Y9 inhibited the proliferation of K562 and K562R cells with IC₅₀ of 1.65 μM and 5.42 μM, respectively. Therefore, 6-phenyl-1H-indazol-3amine as HBM, combined with flexible linker, is a successful strategy contribute to research on T315I mutant resistance, and compound Y9 could be served as a starting point for further optimization.

Keywords: CML; Hinge binding moiety; Phenyl-1H-indazol-3-amine; T315I; mutantFlexible linker.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / metabolism
Benzamides / pharmacology
Binding Sites
Cell Proliferation / drug effects
Drug Design
Fusion Proteins, bcr-abl / antagonists & inhibitors*
Fusion Proteins, bcr-abl / chemistry
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism
Humans
Imatinib Mesylate / pharmacology
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / metabolism
Indazoles / pharmacology*
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Molecular Docking Simulation
Mutation
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / metabolism
Piperazines / pharmacology
Pliability
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*

Substances

Antineoplastic Agents
Benzamides
Indazoles
Piperazines
Protein Kinase Inhibitors
Imatinib Mesylate
Fusion Proteins, bcr-abl