Discovery of a series of benzopyrimidodiazepinone TNK2 inhibitors via scaffold morphing

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

doi:10.1016/j.bmcl.2020.127456

Discovery of a series of benzopyrimidodiazepinone TNK2 inhibitors via scaffold morphing

Bioorg Med Chem Lett. 2020 Oct 1;30(19):127456. doi: 10.1016/j.bmcl.2020.127456. Epub 2020 Jul 31.

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 SYNthesis med chem, 425 Changyang Street, Suzhou Industry Park, Suzhou, Jiangsu, China.
³ Vivid BioSciences, 50 Northern Ave, Boston, MA 02210, USA.
⁴ 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. Electronic address: [email protected].
⁵ 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. Electronic address: [email protected].

PMID: 32739400
DOI: 10.1016/j.bmcl.2020.127456

Abstract

The protein kinase TNK2 (ACK1) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role transmitting cell survival, growth and proliferative signals via modification of multiple downstream effectors by unique tyrosine phosphorylation events. Scaffold morphing based on our previous TNK2 inhibitor XMD8-87 identified urea 17 from which we developed the potent and selective compound 32. A co-crystal structure was obtained showing 32 interacting primarily with the main chain atoms of an alanine residue of the hinge region. Additional H-bonds exist between the urea NHs and the Thr205 and Asp270 residues.

Keywords: Benzopyrimidodiazepinone; Kinase inhibitor; Scaffold morphing; TNK2.

Publication types

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

MeSH terms

Animals
Benzodiazepinones / chemical synthesis
Benzodiazepinones / metabolism
Benzodiazepinones / pharmacology*
Cell Line
Crystallography, X-Ray
Drug Stability
Humans
Male
Mice
Microsomes, Liver / metabolism
Molecular Structure
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Benzodiazepinones
Protein Kinase Inhibitors
Pyrimidines
Tnk2 protein, mouse
Protein-Tyrosine Kinases
TNK2 protein, human