Oleanane has been reported in Upper Cretaceous and Tertiary source rocks and their related oils and has been suggested as a marker for flowering plants. Correspondence of oleanane concentrations relative to the ubiquitous microbial marker 17alpha-hopane with angiosperm diversification (Neocomian to Miocene) suggests that oleanane concentrations in migrated petroleum can be used to identify the maximum age of unknown or unavailable source rock. Rare occurrences of pre-Cretaceous oleanane suggest either that a separate lineage leads to the angiosperms well before the Early Cretaceous or that other plant groups have the rarely expressed ability to synthesize oleanane precursors.
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.
The KEAP1–NRF2-mediated
cytoprotective response plays a
key role in cellular homoeostasis. Insufficient NRF2 signaling during
chronic oxidative stress may be associated with the pathophysiology
of several diseases with an inflammatory component, and pathway activation
through direct modulation of the KEAP1–NRF2 protein–protein
interaction is being increasingly explored as a potential therapeutic
strategy. Nevertheless, the physicochemical nature of the KEAP1–NRF2
interface suggests that achieving high affinity for a cell-penetrant
druglike inhibitor might be challenging. We recently reported the
discovery of a highly potent tool compound which was used to probe
the biology associated with directly disrupting the interaction of
NRF2 with the KEAP1 Kelch domain. We now present a detailed account
of the medicinal chemistry campaign leading to this molecule, which
included exploration and optimization of protein–ligand interactions
in three energetic “hot spots” identified by fragment
screening. In particular, we also discuss how consideration of ligand
conformational stabilization was important to its development and
present evidence for preorganization of the lead compound which may
contribute to its high affinity and cellular activity.
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