Potently inhibiting cancer cell migration with novel 3H-pyrazolo[4,3-f]quinoline boronic acid ROCK inhibitors

Neetu Dayal; Clinton G Mikek; Delmis Hernandez; George A Naclerio; Elizabeth Fei Yin Chu; Brandon A Carter-Cooper; Rena G Lapidus; Herman O Sintim

doi:10.1016/j.ejmech.2019.06.089

Potently inhibiting cancer cell migration with novel 3H-pyrazolo[4,3-f]quinoline boronic acid ROCK inhibitors

Eur J Med Chem. 2019 Oct 15:180:449-456. doi: 10.1016/j.ejmech.2019.06.089. Epub 2019 Jun 29.

Authors

Neetu Dayal¹, Clinton G Mikek¹, Delmis Hernandez¹, George A Naclerio¹, Elizabeth Fei Yin Chu¹, Brandon A Carter-Cooper², Rena G Lapidus², Herman O Sintim³

Affiliations

¹ Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA.
² Translational Core Laboratory, University of Maryland Greenebaum Cancer Center, 655 W Baltimore Street, Baltimore, MD, 21201, USA.
³ Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA; Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, USA; Purdue Institute of Inflammation and Infectious Diseases, Purdue University, West Lafayette, IN, 47907, USA. Electronic address: hsintim@purdue.edu.

PMID: 31330446
DOI: 10.1016/j.ejmech.2019.06.089

Abstract

Rho-associated protein kinases (ROCKs) are ubiquitously expressed in most adult tissues, and are involved in modulating the cytoskeleton, protein synthesis and degradation pathways, synaptic function, and autophagy to list a few. A few ROCK inhibitors, such as fasudil and netarsudil, are approved for clinical use. Here we present a new ROCK inhibitor, boronic acid containing HSD1590, which is more potent than netarsudil at binding to or inhibiting ROCK enzymatic activities. This compound exhibits single digit nanomolar binding to ROCK (Kds < 2 nM) and subnanomolar enzymatic inhibition profile (ROCK2 IC50 is 0.5 nM for HSD1590. Netarsudil, an FDA-approved drug, inhibited ROCK2 with IC50 = 11 nM under similar conditions). Whereas netarsudil was cytotoxic to breast cancer cell line, MDA-MB-231 (greater than 80% growth inhibition at concentrations greater than 5 μM), HSD1590 displayed low cytotoxicity to MDA-MB-231. Interestingly, at 1 μM HSD1590 inhibited the migration of MDA-MB-231 whereas netarsudil did not.

Keywords: Cancer migration; Multi-component reaction; ROCK kinase.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Boronic Acids / chemical synthesis
Boronic Acids / chemistry
Boronic Acids / pharmacology*
Cell Line, Tumor
Cell Movement / drug effects*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / metabolism

Substances

Antineoplastic Agents
Boronic Acids
Protein Kinase Inhibitors
Quinolines
rho-Associated Kinases