Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases

Erra, Montse; Taltavull, Joan; Gréco, Angelique; Bernal, Francisco Javier Valera; Caturla, Juan Francisco; Gràcia, Jordi; Domínguez, María; Sabaté, Mar; Paris, Stéphane; Soria, S; Hernández, Begoña; Armengol, Clara; Cabedo, Judit; Bravo, Mònica; Calama, Elena; Miralpeix, Montserrat; Lehner, Martin D.

doi:10.1021/acsmedchemlett.6b00438

Cited by 24 publications

(38 citation statements)

References 20 publications

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“…LAS191954 is a specific and potent inhibitor of the p110δ catalytic isoform of PI3K with a reported enzymatic potency of 2.6 nM ( 26 ). The compound is 30-fold selective versus the p110β (IC50 94.2 nM) and p110γ (IC50 71.7 nM) isoforms and 3,000-fold over the p110α isoform (IC50 8226 nM).…”

Section: Resultsmentioning

confidence: 99%

“…LAS191954 was synthesized as previously described ( 26 ). For in vivo per os administration, LAS191954 was suspended in 0.5% methylcellulose, 0.1% Tween80.…”

Section: Methodsmentioning

confidence: 99%

“…At randomization and at the end of the treatment period, serum was obtained for determination of circulating antigen-specific IgG, which was performed as described ( 11 ). Compound plasma levels were determined by spectrometry as described ( 26 ) on samples obtained 1 h after the last compound administration. This time point corresponds approximately to the Cmax of the compound in plasma as determined in healthy mouse PK studies (data not shown).…”

Section: Methodsmentioning

confidence: 99%

“…Based on the above considerations, we here evaluated the effect of LAS191954, a recently described novel selective PI3Kδ inhibitor ( 26 ), on clinical aspects of distinct experimental EBA mouse models. Our results indicate that the compound can reverse established immunization-induced disease and prevent disease induced by anti-COL7 antibody transfer.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

et al. 2018

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Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal–epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases.

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Section: Resultsmentioning

confidence: 99%

“…LAS191954 was synthesized as previously described ( 26 ). For in vivo per os administration, LAS191954 was suspended in 0.5% methylcellulose, 0.1% Tween80.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

et al. 2018

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“…Enzymatic Syk kinase activity assays and Syk dependent LAD2 cells degranulation assays were performed as previously described [ 34 ]. PI3Kδ dependent pAkt phosphorylation in macrophage colony-stimulating factor (M-CSF) stimulated THP-1 cells was measured as previously described [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

Application of a phenotypic drug discovery strategy to identify biological and chemical starting points for inhibition of TSLP production in lung epithelial cells

et al. 2018

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Thymic stromal lymphopoietin (TSLP) is a cytokine released by human lung epithelium in response to external insult. Considered as a master switch in T helper 2 lymphocyte (Th2) mediated responses, TSLP is believed to play a key role in allergic diseases including asthma. The aim of this study was to use a phenotypic approach to identify new biological and chemical starting points for inhibition of TSLP production in human bronchial epithelial cells (NHBE), with the objective of reducing Th2-mediated airway inflammation. To this end, a phenotypic screen was performed using poly I:C / IL-4 stimulated NHBE cells interrogated with a 44,974 compound library. As a result, 85 hits which downregulated TSLP protein and mRNA levels were identified and a representative subset of 7 hits was selected for further characterization. These molecules inhibited the activity of several members of the MAPK, PI3K and tyrosine kinase families and some of them have been reported as modulators of cellular phenotypic endpoints like cell-cell contacts, microtubule polymerization and caspase activation. Characterization of the biological profile of the hits suggested that mTOR could be a key activity involved in the regulation of TSLP production in NHBE cells. Among other targeted kinases, inhibition of p38 MAPK and JAK kinases showed different degrees of correlation with TSLP downregulation, while Syk kinase did not seem to be related. Overall, inhibition of TSLP production by the selected hits, rather than resulting from inhibition of single isolated targets, appeared to be due to a combination of activities with different levels of relevance. Finally, a hit expansion exercise yielded additional active compounds that could be amenable to further optimization, providing an opportunity to dissociate TSLP inhibition from other non-desired activities. This study illustrates the potential of phenotypic drug discovery to complement target based approaches by providing new chemistry and biology leads.

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Tandem [3+1+1+1] Heterocyclization of α‐Acyl Ketene Dithioacetals with Ammonia and Methanol: Rapid Assembly of Polysubstituted Pyrimidines

Wang

Zhang

et al. 2022

Eur J Org Chem

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A straightforward copper‐catalyzed aerobic cyclocondensation reaction of α‐acyl ketene dithioacetals with ammonium acetate and methanol was developed for synthesizing highly functionalized pyrimidines. This domino conversion relied on the dual activities of CuCl2, namely Lewis acid and dehydrogenation, which began with single C−S ammonolysis directed by an in situ generated imine, followed by cyclocondensation with aldehyde produced from alcohol and concomitant oxidative dehydrogenation under an oxygen atmosphere. Notably, readily accessible and flexible substrates, common chemical feedstock nitrogen and C1 sources, good functional group tolerance and procedural simplicity exhibit the efficiency and potential application of the new method.

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Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases

Cited by 24 publications

References 20 publications

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Application of a phenotypic drug discovery strategy to identify biological and chemical starting points for inhibition of TSLP production in lung epithelial cells

Tandem [3+1+1+1] Heterocyclization of α‐Acyl Ketene Dithioacetals with Ammonia and Methanol: Rapid Assembly of Polysubstituted Pyrimidines

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