Rapid, auxin-responsive degradation of multiple auxin/indole-3-acetic acid (Aux/IAA) proteins is essential for plant growth and development. Domain II residues were previously shown to be required for the degradation of several Arabidopsis thaliana Aux/IAA proteins. We examined the degradation of additional full-length family members and the proteolytic importance of N-terminal residues outside domain II using luciferase (LUC) fusions. Elimination of domain I did not affect degradation. However, substituting an Arg for a conserved Lys between domains I and II specifically impaired basal degradation without compromising the auxin-mediated acceleration of degradation. IAA8, IAA9, and IAA28 contain domain II and a conserved Lys, but they were degraded more slowly than previously characterized family members when expressed as LUC fusions, suggesting that sequences outside domain II influence proteolysis. We analyzed the degradation of IAA31, with a region somewhat similar to domain II but without the conserved Lys, and of IAA20, which lacks domain II and the conserved Lys. Both IAA20:LUC and epitope-tagged IAA20 were long-lived, and their longevity was not influenced by auxin. Epitope-tagged IAA31 was long-lived, like IAA20, but by contrast, it showed accelerated degradation in response to auxin. The existence of long-lived and auxin-insensitive Aux/IAA proteins suggeststhat they may play a novel role in auxin signaling.

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AMG 579 (1) is a potent and selective phosphodiesterase 10 (PDE10A) inhibitor selected for clinical development for the treatment of schizophrenia. Extensive polymorph and salt screening identified two free-base anhydrous polymorphs (Form 1 and Form 2) that are viable for further development. Crystal structures of these two polymorphs were determined by single-crystal X-ray study. Form 1 and Form 2 are enantiotropically related with the transition temperature between 190 and 210 °C. After full characterization, quality attributes were evaluated, and Form 2, the thermodynamically more stable form at room temperature, was selected for clinical development. A crystallization process for Form 2 was developed, and in situ Raman spectroscopy was used as a PAT tool to monitor and control the physical form. Use of this integrated control strategy allowed access to multikilogram quantities of AMG 579 in the desired form.

Background and objective AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects. Methods In a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects. Results Following a single oral dose of AMG 986, the geometric mean maximum observed concentration ( C max ) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC 0–120h ) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81–0.96) and 0.72 (90% CI 0.57–0.91) for AUC 0–120h and C max , respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity. Conclusion There was a modest 12% decrease in AUC 0–120h and a 28% decrease in C max with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-022-00388-1.