Benzopyrimidodiazepinone inhibitors of TNK2

Brian J Groendyke; Chelsea E Powell; Frederic Feru; Thomas W Gero; Zhengnian Li; Hilary Szabo; Kevin Pang; John Feutrill; Bailing Chen; Bin Li; Nathanael S Gray; David A Scott

doi:10.1016/j.bmcl.2020.126948

Benzopyrimidodiazepinone inhibitors of TNK2

Bioorg Med Chem Lett. 2020 Feb 15;30(4):126948. doi: 10.1016/j.bmcl.2020.126948. Epub 2020 Jan 7.

Authors

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA.
² Vivid BioSciences, 50 Northern Ave, Boston, MA 02210, USA.
³ Northeastern University, 360 Huntington Ave, Boston, MA 02115, USA.
⁴ SYNthesis Med Chem, 425 Changyang Street, Suzhou Industry Park, Suzhou, Jiangsu, China.

PMID: 31928839
DOI: 10.1016/j.bmcl.2020.126948

Abstract

The SAR of a series of benzopyrimidodiazepinone inhibitors of TNK2 was developed, starting from the potent and selective compound XMD8-87. A diverse set of anilines was introduced in an effort to improve the in vivo PK profile and minimize the risk of quinone diimine formation.

Keywords: Benzopyrimidodiazepinone; Kinase inhibitor; TNK2.

MeSH terms

Animals
Azepines / chemistry*
Azepines / metabolism
Azepines / pharmacokinetics
Cell Line, Tumor
Half-Life
Humans
Inhibitory Concentration 50
Mice
Microsomes, Liver / metabolism
Protein Binding
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacokinetics
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship

Substances

Azepines
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
TNK2 protein, human