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.
Zhengnian Li  1 ,  Chelsea E Powell  1 ,  Brian J Groendyke  1 ,  Thomas W Gero  1 ,  Frederic Feru  1 ,  John Feutrill  2 ,  Bailing Chen  2 ,  Bin Li  2 ,  Hilary Szabo  3 ,  Nathanael S Gray  4 ,  David A Scott  5
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.
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