The discovery of Polo-like kinase 4 inhibitors: design and optimization of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H).ones as orally bioavailable antitumor agents.

Abstract

Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved hysicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.

• Authors: Peter B Sampson, Yong Liu, Narendra Kumar Patel, Miklos Feher, Bryan Forrest, Sze-Wan Li, Louise Edwards, Radoslaw Laufer, Yunhui Lang, Fuqiang Ban, Donald E Awrey, Guodong Mao, Olga Plotnikova, Genie Leung, Richard Hodgson, Jacqueline M Mason, Xin Wei, Reza Kiarash, Erin Green, Wei Qiu, Nickolay Y Chirgadze, Tak W Mak, Guohua Pan, Henry W Pauls
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 1 Pg. 130-46 (Jan 08 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 24867403 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Protein Kinase Inhibitors
• Spiro Compounds
• indolin-2-one
• PLK4 protein, human
• Protein Serine-Threonine Kinases

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Biological Availability
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Discovery
• Drug Screening Assays, Antitumor
• HCT116 Cells
• Humans
• Indoles (chemistry, pharmacokinetics, pharmacology)
• MCF-7 Cells
• Mice
• Models, Chemical
• Molecular Structure
• Neoplasms (drug therapy, metabolism, pathology)
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, chemistry, metabolism)
• Rats
• Spiro Compounds (chemistry, pharmacokinetics, pharmacology)
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays