A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins: 1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2 H,3 H-pyrrolo[3,2- b]pyridin-1-yl)-2-[(2 R,5 R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660)

J Med Chem. 2018 Aug 23;61(16):7314-7329. doi: 10.1021/acs.jmedchem.8b00900. Epub 2018 Aug 9.


Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP-XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate 27 (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423).

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • ERG1 Potassium Channel / antagonists & inhibitors
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacokinetics
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Macaca fascicularis
  • Male
  • Mice, Inbred BALB C
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
  • X-Linked Inhibitor of Apoptosis Protein / chemistry
  • X-Linked Inhibitor of Apoptosis Protein / metabolism
  • Xenograft Model Antitumor Assays


  • AT-IAP compound
  • Antineoplastic Agents
  • ERG1 Potassium Channel
  • Heterocyclic Compounds, 2-Ring
  • Inhibitor of Apoptosis Proteins
  • KCNH2 protein, human
  • Piperazines
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human

Associated data

  • ClinicalTrials.gov/NCT02503423