Optimization of benzodiazepinones as selective inhibitors of the X-linked inhibitor of apoptosis protein (XIAP) second baculovirus IAP repeat (BIR2) domain

Robert F Kester; Andrew F Donnell; Yan Lou; Stacy W Remiszewski; Louis J Lombardo; Shaoqing Chen; Nam T Le; Jennifer Lo; John A Moliterni; Xiaochun Han; J Heather Hogg; Weiling Liang; Christophe Michoud; Kenneth C Rupert; Steven Mischke; Kang Le; Martin Weisel; Cheryl A Janson; Christine M Lukacs; Adrian J Fretland; Kyoungja Hong; Ann Polonskaia; Lin Gao; Shirley Li; Dave S Solis; Doug Aguilar; Christine Tardell; Mark Dvorozniak; Shahid Tannu; Edmund C Lee; Andy D Schutt; Barry Goggin

doi:10.1021/jm400732v

Optimization of benzodiazepinones as selective inhibitors of the X-linked inhibitor of apoptosis protein (XIAP) second baculovirus IAP repeat (BIR2) domain

J Med Chem. 2013 Oct 24;56(20):7788-803. doi: 10.1021/jm400732v. Epub 2013 Oct 7.

Affiliation

¹ Departments of Discovery Chemistry, ‡Discovery Technologies, §Non-clinical Safety, Early ADME, and ∥Discovery Oncology, Hoffmann-La Roche Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.

PMID: 24093940
DOI: 10.1021/jm400732v

Abstract

The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.

MeSH terms

Alanine / analogs & derivatives
Alanine / chemical synthesis
Alanine / pharmacokinetics
Alanine / pharmacology
Animals
Apoptosis / drug effects
Benzodiazepinones / chemical synthesis
Benzodiazepinones / pharmacokinetics
Benzodiazepinones / pharmacology
Blotting, Western
Caspase 3 / metabolism
Caspase 7 / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Crystallography, X-Ray
Female
Heterocyclic Compounds / chemical synthesis*
Heterocyclic Compounds / pharmacokinetics
Heterocyclic Compounds / pharmacology*
Humans
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
Inhibitor of Apoptosis Proteins / chemistry
Inhibitor of Apoptosis Proteins / metabolism
Mice
Mice, Nude
Models, Chemical
Models, Molecular
Molecular Structure
Protein Structure, Tertiary
Ubiquitin-Protein Ligases
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

Benzodiazepinones
Heterocyclic Compounds
Inhibitor of Apoptosis Proteins
N-(5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo(b)(1,4)diazepin-3-yl)-2-(methylamino)propanamide
X-Linked Inhibitor of Apoptosis Protein
BIRC2 protein, human
Ubiquitin-Protein Ligases
Caspase 3
Caspase 7
Alanine

Associated data

PDB/4KJU