Modulation of cellular apoptosis with apoptotic protease-activating factor 1 (Apaf-1) inhibitors.
The programmed cell death or apoptosis plays both physiological and pathological roles in biology. Anomalous activation of apoptosis has been associated with malignancies. The intrinsic mitochondrial pathway of apoptosis activation occurs through a multiprotein complex named the apoptosome. We have discovered molecules that bind to a central protein component of the apoptosome, Apaf-1, and inhibits its activity. These new first-in-class apoptosome inhibitors have been further improved by modifications directed to enhance their cellular penetration to yield compounds that decrease cell death, both in cellular models of apoptosis and in neonatal rat cardiomyocytes under hypoxic conditions.
Mondragón
L
L
Department of Medicinal Chemistry, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Orzáez
M
M
Sanclimens
G
G
Moure
A
A
Armiñán
A
A
Sepúlveda
P
P
Messeguer
A
A
Vicent
M J
MJ
Pérez-Payá
E
E
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D053478:Apoptosomes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053477:Apoptotic Protease-Activating Factor 1 / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000737:chemistry; D015687:Cell Hypoxia; D057846:Cell-Penetrating Peptides; D002478:Cells, Cultured; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008968:Molecular Conformation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry; D034444:Peptoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011099:Polyglutamic Acid / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
C506592:APAF1 protein, human; C506594:Apaf1 protein, rat; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D010446:Peptide Fragments; D034444:Peptoids; D054322:tat Gene Products, Human Immunodeficiency Virus; D011099:Polyglutamic Acid; C414409:penetratin