2. Academic Validation
  3. C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays

C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays

  • Eur J Med Chem. 2019 Sep 1;177:316-337. doi: 10.1016/j.ejmech.2019.05.041.
Yann-Vaï Le Bihan 1,  Rachel M Lanigan 1,  Butrus Atrash 1,  Mark G McLaughlin 1,  Srikannathasan Velupillai 2,  Andrew G Malcolm 1,  Katherine S England 3,  Gian Filippo Ruda 2,  N Yi Mok 1,  Anthony Tumber 3,  Kathy Tomlin 1,  Harry Saville 1,  Erald Shehu 1,  Craig McAndrew 1,  LeAnne Carmichael 1,  James M Bennett 3,  Fiona Jeganathan 1,  Paul Eve 1,  Adam Donovan 1,  Angela Hayes 1,  Francesca Wood 1,  Florence I Raynaud 1,  Oleg Fedorov 3,  Paul E Brennan 3,  Rosemary Burke 1,  Rob L M van Montfort 1,  Olivia W Rossanese 1,  Julian Blagg 4,  Vassilios Bavetsias 5
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
  • 2 Structural Genomics Consortium (SGC), University of Oxford, ORCRB Roosevelt Drive, Oxford, OX3 7DQ, UK.
  • 3 Structural Genomics Consortium (SGC), University of Oxford, ORCRB Roosevelt Drive, Oxford, OX3 7DQ, UK; Target Discovery Institute (TDI), Nuffield Department of Medicine, University of Oxford, NDMRB, Roosevelt Drive, Oxford, OX3 7FZ, UK.
  • 4 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK. Electronic address: julian.blagg@icr.ac.uk.
  • 5 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK. Electronic address: vassilios.bavetsias@icr.ac.uk.
PMID: 31158747 DOI: 10.1016/j.ejmech.2019.05.041
Abstract

Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily Enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.

Keywords

Histone demethylases; KDM inhibitors; KDM4 subfamily; KDM5 subfamily; Pyridopyrimidinones.

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