Discovery of potent and selective PKC-θ inhibitors

Cywin, Charles L.; Dahmann, Georg; Prokopowicz, Anthony S.; Young, Erick R.R.; Magolda, Ronald L.; Cardozo, Mario; Cogan, Derek A.; DiSalvo, Darren; Ginn, John D.; Kashem, Mohammed A.; Wolak, John P.; Homon, Carol; Farrell, Thomas M.; Grbic, Heather; Hu, Han-Bo; Kaplita, Paul V.; Liu, Lisa H.; Spero, Denice M.; Jeanfavre, Deborah D.; O’Shea, Kathy; White, Della; Woska, Joseph R.; Brown, Marie

doi:10.1016/j.bmcl.2006.09.056

Cited by 67 publications

(41 citation statements)

References 8 publications

(5 reference statements)

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“…Taken together, these evidences validate PKCθ as a particularly attractive target to selectively manipulate T eff cell functions that are relevant to pathogenesis of different diseases, including, as our results suggested, muscular dystrophy. Noteworthy, a large effort is now devoted to the synthesis of pharmacological PKCθ inhibitors, to be used for anti-inflammatory therapies, and several PKCθ inhibitors have been identified and reported in recent literature (Boschelli et al, 2010, Chand et al, 2012, Curnock et al, 2014, Cywin et al, 2007, George et al, 2015, Hage-Sleiman et al, 2015, Jimenez et al, 2013, Katoh et al, 2016). Some of them bind selectively PKCθ while others are non-selective in nature.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

et al. 2017

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Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.Research in contextDuchenne muscular dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a “cure” for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C θ (PKCθ), an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.

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Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

et al. 2017

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“…Human TNF-α (210-TA) was purchased from R&D Systems and added to cocultures where indicated. The PKC-θ inhibitor, compound 20, was provided by Boehringer-Ingelheim Pharmaceuticals and dissolved in DMSO (50). T cells were pretreated for 30 min at a concentration of 1 μM at 37°C and washed three times.…”

Section: Methodsmentioning

confidence: 99%

Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function

Zanin-Zhorov

Lin

Scher

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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+ CD25 high regulatory T cell (Treg) suppression of inflammation depends on T-cell receptor-mediated Nuclear Factor of Activated T cells c1 (NFATc1) activation with reduced Akt activity. We investigated the role of the scaffold protein Disc large homolog 1 (Dlgh1) in linking the T-cell receptor to this unique signaling outcome. The Treg immunological synapse (IS) recruited fourfold more Dlgh1 than conventional CD4 + T-cell IS. Tregs isolated from patients with active rheumatoid arthritis, or treated with tumor necrosis factor-α, displayed reduced function and diminished Dlgh1 recruitment to the IS. Furthermore, Dlgh1 silencing abrogated Treg function, impaired NFATc1 activation, reduced phosphatase and tensin homolog levels, and increased Akt activation. Dlgh1 operates independently of the negative feedback pathway mediated by the related adapter protein Carma1 and thus presents an array of unique targets to selectively manipulate Treg function.immunology | T-cell receptor signaling | supported planar bilayers

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“…3), where X was nitro, as PKC inhibitors [59,60]. While no structure-activity relationships (SAR) could be deduced from the applications, initial SAR data was reported in a subsequent paper [61]. Retaining a 4-[(aminomethyl)-cyclohexyl]methyl group at C-4 of the pyrimidine and varying the substituents on the benzyl amine at C-2 showed that ortho substituents were favored.…”

Section: Boehringer Ingleheim Pkc Inhibitorsmentioning

confidence: 98%

Small Molecule Inhibitors of PKCθ as Potential Antiinflammatory Therapeutics

Boschelli¹

2009

CTMC

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Members of the protein kinase C (PKC) family of serine/threonine kinases have been targeted for drug discovery for over 20 years, initially focusing on inhibitors of the classic PKCs, which include the alpha, beta and gamma isoforms. Recently, inhibition of the activity of the novel PKC isoforms, namely Theta, delta, epsilon and eta has become a focus of research. PKCTheta, first identified in 1992, is a key enzyme in the regulation of T cell activation and survival. While T cells play critical roles in initiating and controlling the immune response, inappropriate or extended stimulation of T cells is responsible for many chronic inflammatory diseases. Mice with an engineered deficiency in PKCTheta have reduced incidence and severity of several inflammatory disorders including asthma, arthritis, inflammatory bowel disease, multiple sclerosis, and allograft rejection. This review summarizes the efforts directed towards the design of small molecule PKCTheta inhibitors as potential therapeutic agents.

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Discovery of potent and selective PKC-θ inhibitors

Cited by 67 publications

References 8 publications

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function

Small Molecule Inhibitors of PKCθ as Potential Antiinflammatory Therapeutics

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Discovery of potent and selective PKC-θ inhibitors

Cited by 67 publications

References 8 publications

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function

Small Molecule Inhibitors of PKC&#952; as Potential Antiinflammatory Therapeutics

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Small Molecule Inhibitors of PKCθ as Potential Antiinflammatory Therapeutics