Last update 01 Nov 2024

PKCθ

Last update 01 Nov 2024

Basic Info

Synonyms

nPKC-theta, PRKCQ, PRKCT

+ [4]

Introduction

Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates in the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylates CCDC88A/GIV and inhibits its guanine nucleotide exchange factor activity (PubMed:23509302).

Drugs associated with PKCθ

BMS-986447

Target

PKCθ

Mechanism

PKCθ inhibitors

Active Org.

Bristol Myers Squibb Co.

Originator Org.

Bristol Myers Squibb Co.

Active Indication-

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

EXS4318

Target

PKCθ

Mechanism

PKCθ inhibitors

Active Org.

Exscientia Plc

Originator Org.

Exscientia Plc

Active Indication

Immune System Diseases [+1]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

PKCθ Inhibitor (BMS)

Target

PKCθ

Mechanism

PKCθ inhibitors

Active Org.

Bristol Myers Squibb Co.

Originator Org.

Bristol Myers Squibb Co.

Active Indication

Autoimmune Diseases

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with PKCθ

NCT05760937 / CompletedPhase 1

A Phase 1 Randomized, Double-blind, Placebo-controlled, First-in-human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single, Ascending Doses of BMS-986447 in Healthy Adult Participants

The purpose of the study is to evaluate the safety, tolerability and drug levels of single, oral doses of BMS-986447 in healthy participants.

Start Date10 Mar 2023

Sponsor / Collaborator

Bristol Myers Squibb Co.

NCT02502188 / TerminatedPhase 1

A Phase 1, Multicenter, Randomized, Double-blind, Placebo-controlled, Single and Multiple Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of CC-90005 in Healthy Subjects and Subjects With Moderate to Severe Plaque-type Psoriasis

To evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of CC-90005 in healthy subjects and subjects with moderate to severe plaque-type psoriasis.

Start Date17 Jul 2015

Sponsor / Collaborator

Celgene Corp.

100 Clinical Results associated with PKCθ

100 Translational Medicine associated with PKCθ

0 Patents (Medical) associated with PKCθ

606

Literatures (Medical) associated with PKCθ

31 Dec 2024·Hematology

Construction of a five-gene-based prognostic model for relapsed/refractory acute lymphoblastic leukemia

Article

Author: Li, Ying ; Zhou, Bi ; Fang, Jing ; Wu, De ; Min, BoJie ; Chen, Qin ; Huang, Jin ; Zhu, Feng ; Liu, WenYuan

BACKGROUNDRelapsed/refractory acute lymphoblastic leukemia (R/R ALL) continues to be a major cause of mortality in children worldwide, with around 15% of ALL patients experiencing relapse and approximately 10% eventually dying from the disease. Early identification of R/R ALL in children has posed a longstanding clinical challenge.METHODGenetic analysis of survival outcomes in pediatric patients with ALL from the TARGET-ALL dataset revealed five risk score factors identified through the intersection of differential genes (relapse/non-relapse) from the GSE17703 and GSE6092 databases. A risk score equation was formulated using these factors and validated against prognostic data from 46 ALL cases at our institution. Patients from multiple datasets were stratified into high and low-score groups based on this equation. Protein-protein interaction networks (PPI) were then constructed using the intersecting differential genes from all three datasets to identify hub nodes and predict interacting transcription factors. Additionally, genes related to cell pyroptosis with varying expression across these datasets were screened, and a multifactorial ROC curve (incorporating risk score and differential expression of pyroptosis-related genes) was generated. Furthermore, relationships among variables in the predictive model were depicted using a nomogram, and model efficacy was assessed through decision curve analysis (DCA).RESULTSBy analyzing the TARGET-ALL, GSE17703, and GSE6092 databases, we developed a prognostic risk assessment model for pediatric ALL incorporating BAG2, EPHA4, FBXO9, SNX10, and WNK1. Validation of this model was conducted using data from 46 pediatric ALL cases obtained from our institution. Following the identification of 27 differentially expressed genes, we constructed a PPI and identified the top 10 hub genes (PTPRC, BTK, LCK, PRKCQ, CD3D, CD27, CD3G, BLNK, RASGRP1, VPREB1). Using this network, we predicted the top 5 transcription factors (HOXB4, MYC, SOX2, E2F1, NANOG). ROC and DCA were conducted on pyroptosis-related genes exhibiting differential expression and risk scores. Subsequently, a nomogram was generated, demonstrating the effectiveness of the risk score in predicting prognosis for pediatric ALL patients.CONCLUSIONSWe have developed a risk prediction model for pediatric R/R ALL utilizing the genes BAG2, EPHA4, FBXO9, SNX10, and WNK1. This model provides a scientific foundation for early identification of R/R ALL in children.

15 Sep 2024·medRxiv : the preprint server for health sciences

A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population.

Article

Author: Pedretti, Sarah ; Sarah, Pedretti ; Day, Cascia ; Ramsay, Michèle ; Panieri, Angelica ; Freercks, Robert ; Micklesfield, Lisa K ; Choudhury, Ananyo ; Engelbrecht, Adelein ; Lisa K Micklesfield ; Mugo, Jacquiline W ; Ribeiro, Melissa ; Cotchbos, Christian ; Peter, Jonny ; Deetlefs, Maria ; Geraty, Sian

BackgroundAngiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population.MethodsThe GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls).ResultsNo SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10^-06). Some of these SNPs were found to be located close to the genes PRKCQ and RIMS1, previously linked with drug-induced angioedema, and also close to the CSMD1 gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs.ConclusionsOur results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.

06 Sep 2024·Medicine

Construction of thyroid cancer classification and iodine metabolism related diagnostic model using thyroid differentiation score and bioinformation.

Article

Author: Wang, Pan-Pan ; Zhang, Qiu-Ying ; Gao, De ; Yan, Hai-Chao ; Huo, Da-Wei ; Li, Yue ; Wang, Yan ; Zhang, Qiang

To more accurately diagnose and treat patients with different subtypes of thyroid cancer, we constructed a diagnostic model related to the iodine metabolism of THCA subtypes. THCA expression profiles, corresponding clinicopathological information, and single-cell RNA-seq were downloaded from TCGA and GEO databases. Genes related to thyroid differentiation score were obtained by GSVA. Through logistic analyses, the diagnostic model was finally constructed. DCA curve, ROC curve, machine learning, and K-M analysis were used to verify the accuracy of the model. qRT-PCR was used to verify the expression of hub genes in vitro. There were 104 crossover genes between different TDS and THCA subtypes. Finally, 5 genes (ABAT, CHEK1, GPX3, NME5, and PRKCQ) that could independently predict the TDS subpopulation were obtained, and a diagnostic model was constructed. ROC, DCA, and RCS curves exhibited that the model has accurate prediction ability. K-M and subgroup analysis results showed that low model scores were strongly associated with poor PFI in THCA patients. The model score was significantly negatively correlated with T cell follicular helper. In addition, the diagnostic model was significantly negatively correlated with immune scores. Finally, the results of qRT-PCR corresponded with bioinformatics results. This diagnostic model has good diagnostic and prognostic value for THCA patients, and can be used as an independent prognostic indicator for THCA patients.

News (Medical) associated with PKCθ

28 Nov 2023

·www.biospace.com

Evommune and Accutar Biotechnology Announce AI Drug Discovery Collaboration

Evommune will leverage Accutar's AI-empowered drug discovery platform for therapies targeting chronic inflammatory diseases PALO ALTO, Calif. and CRANBURY, N.J., Nov. 28, 2023 /PRNewswire/ -- Evommune, Inc., a biotechnology company discovering and developing new ways to treat immune-mediated inflammatory diseases, and Accutar Biotechnology Inc., a company focusing on artificial intelligence (AI)-empowered drug discovery, today announced a new strategic partnership focused on the discovery of novel small molecule drug candidates in chronic inflammatory diseases. The collaboration will leverage Accutar's proprietary AI platform as well as Evommune's expertise in the design and development of novel oral small molecule treatments against targets that are the root cause of chronic immune-mediated inflammatory diseases. Terms of the agreement will not be disclosed. "We are excited to partner with Accutar, a leader in accelerating drug discovery, as we work to identify and validate novel targets that could have a profound impact on chronic inflammatory diseases," said Jeegar Patel, Ph.D., Chief Scientific Officer of Evommune. "Accutar has a highly sophisticated hybrid approach of computational drug design and wet lab validation, and we plan to leverage this to overcome the limitations of traditional drug discovery methods on our targets of interest – allowing us to more efficiently design safe and efficacious therapies for complex chronic inflammatory diseases. Accutar is a team we know well, having collaborated with them on our current program targeting PKCθ, and we are thrilled to be expanding our partnership in a broader capacity." "Chronic inflammatory diseases represent the greatest threat to human health today, with nearly 60 percent of people in the U.S. alone suffering from at least one chronic condition," said Jie Fan, Ph.D., Chief Executive Officer of Accutar. "We look forward to partnering with Evommune, a company with in-depth understanding in inflammatory diseases and extensive expertise in clinical development. By combining Evommune's deep biological insights with our AI-empowered medicinal chemistry engine, and its application to the discovery and development of clinically differentiated medicine, we have great confidence we'll be able to develop the next generation of therapies for chronic inflammatory diseases." About Evommune, Inc. Evommune, Inc., a Palo Alto based biotech company, is creating game-changing science to treat immune-mediated inflammatory diseases by discovering, developing, and delivering therapies that address symptoms and halt progressive disease. For more information, please visit Evommune.com. About Accutar Biotechnology, Inc. Accutar is a clinical stage biotech company focused on AI-empowered drug discovery, and its application to the discovery and development of clinically differentiated medicines. To learn more about Accutar, please visit us at AccutarBio.com. Contact: Paul Laland 415.519.6610 Paul.laland@evommune.com Jiaqi Ren media@accutarbio.com

27 Apr 2023

·www.pharmaceutical-technology.com

Evommune gains funding to accelerate therapies for chronic inflammatory diseases

Evommune focuses on the development of therapies to treat chronic inflammatory diseases. Credit: MasterTux from Pixabay. Evommune has received $50m in Series B financing to accelerate the development of therapies for the treatment of chronic inflammatory diseases. Co-led by new investor Arix Bioscience and current investors EQT Life Sciences and SymBiosis, the financing round also included new and existing investors such as Amplitude Ventures. Recommended Reports Reports LOA and PTSR Model - Gene Therapy to Activate gp91phox for Chronic Granulomatous Disease GlobalData Reports Innovation in Pharmaceuticals: immunotherapy for neurodegenerative disease GlobalData View all Pivotal bioVenture Partners and Andera Partners also participated in the company’s Series A funding round. Arix Bioscience managing director Mark Chin stated: “As a new investor in Evommune, we are excited to partner with the company’s experienced leadership team, which leverages a unique human tissue screening platform to curate its drug discovery and translational medicine decisions.” The funding will allow Evommune to advance three prioritised pipeline programmes that are focused on inflammatory diseases. One of these programmes includes EVO101, a novel small molecule inhibitor that specifically targets the interleukin 1 receptor-associated kinase 4 (IRAK4) gene. EVO101 is currently under assessment in a Phase 2a proof-of-concept trial involving patients diagnosed with atopic dermatitis. The company plans to release data from the trial later in 2023. The company is also assessing the preclinical molecule, EVO756, which is designed to selectively modulate MRGPRX2 and target mast cells to treat diseases such as chronic spontaneous urticaria and interstitial cystitis. The firm’s pipeline also includes a discovery-stage programme focused on autoimmune diseases through PKCθ. Evommune president and CEO Luis Peña stated: “Evommune has multiple value-creating milestones planned over the next two years. We appreciate the continued support of our existing investors, and welcome new investors who share the vision and excitement about our programmes to evolve the immunology landscape.”

Phase 2ImmunotherapyGene Therapy

26 Apr 2023

·www.biospace.com

Evommune Closes $50 Million Series B Financing to Advance Broad Pipeline of Therapies to Treat Chronic Inflammatory Diseases

Financing co-led by Arix Bioscience, EQT Life Sciences and SymBiosis, with participation from new and existing investors including Amplitude Ventures, and Series A leads Pivotal bioVenture Partners and Andera Partners Capital on-hand provides strong financial position through multiple value-creating milestones across immunology-focused pipeline PALO ALTO, Calif., April 26, 2023 /PRNewswire/ --Evommune, Inc., a clinical-stage biotechnology company discovering and developing new ways to treat inflammatory diseases, today announced the completion of a $50 million Series B financing. The financing was co-led by new investor Arix Bioscience and current investors EQT Life Sciences and SymBiosis, with participation from new and existing investors including Amplitude Ventures, and Series A leads Pivotal bioVenture Partners and Andera Partners. "As a new investor in Evommune, we are excited to partner with the company's experienced leadership team, which leverages a unique human tissue screening platform to curate its drug discovery and translational medicine decisions," said Mark Chin, Managing Director at Arix Bioscience. "We believe Evommune is well-positioned to deliver on the promise of its lead investigational medicine, EVO101, targeting interleukin 1 receptor-associated kinase 4 (IRAK4), in addition to rapidly advancing the development of its other compelling programs targeting MRGPRX2 and protein kinase C (PKC) theta (PKCθ)." The capital raised will support Evommune's three prioritized pipeline programs targeting highly prevalent inflammatory diseases, including EVO101, a novel small molecule inhibitor of the IRAK4. This molecule is being evaluated in a Phase 2a proof-of-concept trial in patients with atopic dermatitis, with data expected later this year. In addition, Evommune is evaluating EVO756, a preclinical molecule designed to target mast cells by selectively modulating MRGPRX2 to treat chronic spontaneous urticaria and interstitial cystitis, and a discovery program targeting autoimmune diseases via PKCθ. "Worldwide, three out of five people die from chronic inflammatory diseases, so continuing innovation in the space is vital. With this financing we are poised to be at the forefront of this movement with funds supporting the rapid progression of our broad pipeline well into 2025," said Luis Peña, President and Chief Executive Officer of Evommune. "Evommune has multiple value-creating milestones planned over the next two years. We appreciate the continued support of our existing investors, and welcome new investors who share the vision and excitement about our programs to evolve the immunology landscape." About Evommune, Inc. Evommune, Inc. is a private clinical-stage biotechnology inventing new ways to treat inflammatory diseases. The company is evolving immunology through its unique and dynamic human tissue-based approach to discovering, developing, and delivering therapies that address symptoms and halt progressive disease. Evommune was founded in 2020 by an industry-leading team of R&D experts and biotech company builders, and is headquartered in Palo Alto, California. For more information, visit .

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PKCθ

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