GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)

J Med Chem. 2017 Nov 22;60(22):9162-9183. doi: 10.1021/acs.jmedchem.7b00796. Epub 2017 Sep 21.

Abstract

Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • CREB-Binding Protein / antagonists & inhibitors*
  • CREB-Binding Protein / chemistry
  • Dogs
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • HEK293 Cells
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • Protein Domains
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • RNA / genetics
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • GNE-781
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Pyrazoles
  • Pyridines
  • RNA
  • CREB-Binding Protein