Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma

Perry, Matthew W. D.; Björhall, Karin; Bold, Peter; Brülls, Mikael; Börjesson, Ulf; Carlsson, Johan; Chang, Hui-Fang; Chen, Yunhua; Eriksson, Anders; Fihn, Britt-Marie; Fransson, Rebecca; Fredlund, Linda; Ge, H.; Huang, Haijuan; Karabelas, Kostas; Bergström, Eva Lamm; Lever, Sarah; Lindmark, Helena; Mogemark, Mickael; Nikitidis, Antonios; Palmgren, Anna-Pia; Pemberton, Nils; Petersen, J.; Blomqvist, M.; Smith, Reed W.; Thomas, Matthew; Ullah, Victoria; Tyrchan, Christian; Wennberg, Tiiu; Eriksson, Annika Westin; Yang, Wenzhen; Zhao, Suoqi; Öster, Linda

doi:10.1021/acs.jmedchem.1c00434

Cited by 26 publications

(21 citation statements)

References 24 publications

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“…Although p110γ and p110δ are preferentially expressed in immune cells, p110γ/p110δ inhibitors targeting these isoforms are reported to inhibit inflammatory activity in autoimmune and inflammatory diseases models by affecting the adaptive and innate immune response, such as collagen-induced arthritis, ovalbumin-induced asthma, microbiota-dependent colitis and systemic lupus erythematosus models (31,32), leading to potential therapeutic effects in multiple inflammatory and autoimmune diseases. Furthermore, clinical trials have also shown promising effects of PI3Kδ/γ inhibitors on immune disorders such as asthma, Sjögren's syndrome and allergic rhinitis (33)(34)(35), showing significant potential of PI3K inhibitors for clinical use. Despite this, not all PI3K inhibitors can produce a good response in treatment.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model

et al. 2023

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Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)-related non-caseating granulomas. Phosphoinositide-3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL-101 (PI3Kδ inhibitor) or AS-605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence-activated cell sorting analysis and reverse transcription-quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA-induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4 + CD25 -T cells and CD4 + CD25 + T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL-101/AS-605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL-101 was more effective in immune modulation compared with AS-605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs-mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune-therapeutic principle for sarcoidosis in the future.

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Section: Discussionmentioning

confidence: 99%

Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model

et al. 2023

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“…Data extraction of appropriate Buchwald–Hartwig amination reactions led to a similar distribution of articles to the SMCC data set (Figure ). From 57 articles and 69 reactions, ,,,,− the largest proportion, again, are localized in the lowest mol % category of 0–1 mol %. There are several sources that involve the use of other metal additives (CuI and Zn(OTf) 2 ), which skew the data, being used in 50 (0.5 equiv.)…”

Section: Buchwald–hartwig Aminationmentioning

confidence: 92%

“…As a comparison to the previous data set, ca. 15 additional papers were surveyed from the Journal of Medicinal Chemistry ( JMC ) for both SMCC reactions ,,− and Buchwald–Hartwig amination reactions. − ,− As the previous data were found from a variety of journals, although largely catalysis specific, we were interested to see how different these would be compared to papers only reported in JMC and if there was a difference in mol % and ppm catalyst levels. Finding more papers with a greater focus on catalyst usage, rather than catalyst optimization, reveals a different angle to this study.…”

Section: Further Analysis Of Selected Articles Reported In the Journa...mentioning

confidence: 99%

Pd-Catalyzed Cross-Couplings: On the Importance of the Catalyst Quantity Descriptors, mol % and ppm

Horbaczewskyj

Fairlamb

2022

Org. Process Res. Dev.

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This Review examines parts per million (ppm) palladium concentrations in catalytic cross-coupling reactions and their relationship with mole percentage (mol %). Most studies in catalytic cross-coupling chemistry have historically focused on the concentration ratio between (pre)catalyst and the limiting reagent (substrate), expressed as mol %. Several recent papers have outlined the use of “ppm level” palladium as an alternative means of describing catalytic cross-coupling reaction systems. This led us to delve deeper into the literature to assess whether “ppm level” palladium is a practically useful descriptor of catalyst quantities in palladium-catalyzed cross-coupling reactions. Indeed, we conjectured that many reactions could, unknowingly, have employed low “ppm levels” of palladium (pre)catalyst, and generally, what would the spread of ppm palladium look like across a selection of studies reported across the vast array of the cross-coupling chemistry literature. In a few selected examples, we have examined other metal catalyst systems for comparison with palladium.

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“…The switch from a five-membered to a six-membered lactam in N -aryl lactams leads to a change from a coplanar to an out-of-plane conformation as a result of the increased steric strain . As illustrated by the matched molecular pair of 49 and 50 , the γ-lactam 49 is, unexpectedly, more lipophilic, less soluble, and higher melting than the corresponding δ-lactam 50 …”

Section: Conformational Design By Adding a Single Carbon Atommentioning

confidence: 99%

The Role of Allylic Strain for Conformational Control in Medicinal Chemistry

et al. 2023

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It is axiomatic in medicinal chemistry that optimization of the potency of a small molecule at a macromolecular target requires complementarity between the ligand and target. In order to minimize the conformational penalty on binding, both enthalpically and entropically, it is therefore preferred to have the ligand preorganized in the bound conformation. In this Perspective, we highlight the role of allylic strain in controlling conformational preferences. Allylic strain was originally described for carbon-based allylic systems, but the same principles apply to other types of structure with sp 2 or pseudo-sp 2 arrangements. These systems include benzylic (including heteroaryl methyl) positions, amides, N-aryl groups, aryl ethers, and nucleotides. We have derived torsion profiles from small molecule X-ray structures for these systems. Through multiple examples, we show how these effects have been applied in drug discovery and how they can be used prospectively to influence conformation in the design process.

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Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma

Cited by 26 publications

References 24 publications

Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model

Inhibition of phosphoinositide‑3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model

Pd-Catalyzed Cross-Couplings: On the Importance of the Catalyst Quantity Descriptors, mol % and ppm

The Role of Allylic Strain for Conformational Control in Medicinal Chemistry

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