Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP).
Emiliano TamaniniIldiko M BuckGianni ChessariElisabetta ChiarparinJames E H DayMartyn FredericksonCharlotte M Griffiths-JonesKeisha HearnTom D HeightmanAman IqbalChristopher N JohnsonEdward J LewisVanessa MartinsTorren PeakmanMichael ReaderSharna J RichGeorge A WardPamela A WilliamsNicola E WilsherPublished in: Journal of medicinal chemistry (2017)
XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies, and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.
Keyphrases
- small molecule
- protein protein
- cell death
- oxidative stress
- cell cycle arrest
- endoplasmic reticulum stress
- anti inflammatory
- signaling pathway
- high resolution
- amino acid
- transcription factor
- pi k akt
- binding protein
- cell proliferation
- emergency department
- computed tomography
- healthcare
- poor prognosis
- molecular dynamics
- molecular dynamics simulations
- magnetic resonance imaging
- induced apoptosis
- mass spectrometry
- social media
- quantum dots
- long non coding rna
- combination therapy
- replacement therapy
- young adults