2. Academic Validation
  3. Discovery of a series of benzopyrimidodiazepinone TNK2 inhibitors via scaffold morphing

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

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: nathanael_gray@dfci.harvard.edu.
  • 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: davida_scott@dfci.harvard.edu.
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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