The regulatory domain of the bifunctional threonine-sensitive aspartate kinase homoserine dehydrogenase contains two homologous subdomains defined by a common loop-alpha helix-loop-beta strand-loop-beta strand motif. This motif is homologous with that found in the two subdomains of the biosynthetic threonine-deaminase regulatory domain. Comparisons of the primary and secondary structures of the two enzymes allowed us to predict the location and identity of the amino acid residues potentially involved in two threonine-binding sites of Arabidopsis thaliana aspartate kinase-homoserine dehydrogenase. These amino acids were then mutated and activity measurements were carried out to test this hypothesis. Steady-state kinetic experiments on the wild-type and mutant enzymes demonstrated that each regulatory domain of the monomers of aspartate kinase-homoserine dehydrogenase possesses two nonequivalent threonine-binding sites constituted in part by Gln(443) and Gln(524). Our results also demonstrated that threonine interaction with Gln(443) leads to inhibition of aspartate kinase activity and facilitates the binding of a second threonine on Gln(524). Interaction of this second threonine with Gln(524) leads to inhibition of homoserine dehydrogenase activity.
The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure−activity relationships and structure−property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.
Oral PI3Kδ inhibitors such
as Idelalisib and Duvelisib have
shown efficacy as anticancer agents and Idelalisib has been approved
for the treatment of three B-cell cancers. However, Idelalisib has
a black box warning on its product label regarding the risks of fatal
and serious toxicities including hepatic toxicity, severe diarrhea,
colitis, pneumonitis, infections, and intestinal perforation. Some
of these side effects are mechanism-related and could hinder the development
of Idelalisib for less severe conditions. For respiratory diseases,
compounds administered by inhalation are delivered directly to the
site of action and may improve the therapeutic index of a drug, minimizing
undesired side effects. This work describes the discovery and optimization
of inhaled PI3Kδ inhibitors intended for the treatment of severe
asthma and COPD. Once the potency was in the desired range, efforts
were focused on identifying the particular physicochemical properties
that could translate into better lung retention. This medicinal chemistry
exercise led to the identification of LAS195319 as a candidate for
clinical development.
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