The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent

Peter B Sampson; Yong Liu; Bryan Forrest; Graham Cumming; Sze-Wan Li; Narendra Kumar Patel; Louise Edwards; Radoslaw Laufer; Miklos Feher; Fuqiang Ban; Donald E Awrey; Guodong Mao; Olga Plotnikova; Richard Hodgson; Irina Beletskaya; Jacqueline M Mason; Xunyi Luo; Vincent Nadeem; Xin Wei; Reza Kiarash; Brian Madeira; Ping Huang; Tak W Mak; Guohua Pan; Henry W Pauls

The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent

J Med Chem. 2015 Jan 8;58(1):147-69.

PMID: 25723005

Abstract

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Biological Availability
Cell Line, Tumor
Cell Survival / drug effects
Dogs
Dose-Response Relationship, Drug
Drug Discovery
Female
HCT116 Cells
Humans
Indazoles / chemistry
Indazoles / pharmacokinetics
Indazoles / pharmacology*
Indoles / chemistry
Indoles / pharmacokinetics
Indoles / pharmacology*
MCF-7 Cells
Male
Mice, Nude
Mice, SCID
Models, Chemical
Molecular Structure
Neoplasms / drug therapy*
Neoplasms / metabolism
Neoplasms / pathology
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / analysis*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / metabolism
Rats
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one
Antineoplastic Agents
Indazoles
Indoles
Protein Kinase Inhibitors
indolin-2-one
PLK4 protein, human
Protein Serine-Threonine Kinases