Molecular design and anticancer activities of small-molecule monopolar spindle 1 inhibitors: A Medicinal chemistry perspective

Shutao Wang; Muxin Zhang; Di Liang; Wei Sun; Chaozai Zhang; Mengnan Jiang; Junli Liu; Jiaguo Li; Chenchen Li; Xiaohong Yang; Xiaoping Zhou

doi:10.1016/j.ejmech.2019.04.047

Molecular design and anticancer activities of small-molecule monopolar spindle 1 inhibitors: A Medicinal chemistry perspective

Eur J Med Chem. 2019 Aug 1:175:247-268. doi: 10.1016/j.ejmech.2019.04.047. Epub 2019 Apr 20.

Authors

Affiliations

¹ School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China.
² School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China. Electronic address: zhouxp@jlu.edu.cn.

PMID: 31121430
DOI: 10.1016/j.ejmech.2019.04.047

Abstract

As a dual-specificity protein kinase, monopolar spindle 1 (Mps1) is one of the main kinases involved in kinetochore localization and the spindle assembly checkpoint (SAC). Cancer cells often display chromosomal instability, which is a consequence of disfunction of cell cycle checkpoints partially. Mps1 is overexpressed in multiple cancer types to face the pressure from aberrant chromosomes and centrosomes. Therefore, Mps1 is a potential targeting approach to cancer treatment. Several compounds targeting Mps1 have been developed and approved to begin clinical trials for advanced nonhaematologic malignancies treatments, including but not limited to triple negative breast cancer (TNBC) treatment. In this review, we will highlight typical Mps1 inhibitors developed during the last decade and provide a reference for more potential Mps1 inhibitors exploration in the future.

Keywords: Cancer; Drug design; Mps1/TTK inhibitors; Structure−activity relationship.

Publication types

Review

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Drug Design*
Drug Resistance
Humans
M Phase Cell Cycle Checkpoints / drug effects
Protein Conformation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / chemistry
Spindle Apparatus / drug effects*
Structure-Activity Relationship
Triple Negative Breast Neoplasms / pathology

Substances

Antineoplastic Agents
Cell Cycle Proteins
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
TTK protein, human