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)

Christopher N Johnson; Jong Sook Ahn; Ildiko M Buck; Elisabetta Chiarparin; James E H Day; Anna Hopkins; Steven Howard; Edward J Lewis; Vanessa Martins; Alessia Millemaggi; Joanne M Munck; Lee W Page; Torren Peakman; Michael Reader; Sharna J Rich; Gordon Saxty; Tomoko Smyth; Neil T Thompson; George A Ward; Pamela A Williams; Nicola E Wilsher; Gianni Chessari

doi:10.1021/acs.jmedchem.8b00900

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.

Authors

Christopher N Johnson¹, Jong Sook Ahn¹, Ildiko M Buck¹, Elisabetta Chiarparin¹, James E H Day¹, Anna Hopkins¹, Steven Howard¹, Edward J Lewis¹, Vanessa Martins¹, Alessia Millemaggi¹, Joanne M Munck¹, Lee W Page¹, Torren Peakman¹, Michael Reader¹, Sharna J Rich¹, Gordon Saxty¹, Tomoko Smyth¹, Neil T Thompson¹, George A Ward¹, Pamela A Williams¹, Nicola E Wilsher¹, Gianni Chessari¹

Affiliation

¹ Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road , Cambridge CB4 0QA , United Kingdom.

PMID: 30091600
DOI: 10.1021/acs.jmedchem.8b00900

Abstract

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

Substances

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