Last update 21 Mar 2024

DGKA

diacylglycerol kinase alpha

Last update 21 Mar 2024

Basic Info

Synonyms

80 kDa diacylglycerol kinase, DAG kinase alpha, DAGK

+ [5]

Introduction

Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:2175712, PubMed:15544348). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (PubMed:2175712, PubMed:15544348). Also plays an important role in the biosynthesis of complex lipids (Probable). Can also phosphorylate 1-alkyl-2-acylglycerol in vitro as efficiently as diacylglycerol provided it contains an arachidonoyl group (PubMed:15544348). Also involved in the production of alkyl-lysophosphatidic acid, another bioactive lipid, through the phosphorylation of 1-alkyl-2-acetyl glycerol (PubMed:22627129).

Drugs associated with DGKA

BAY-2862789

Target

DGKA

Mechanism

DGKA inhibitors

Active Org.

Bayer AG [+1]

Originator Org.

Bayer Pharmaceuticals

Active Indication

Advanced Malignant Solid Neoplasm [+2]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GS-9911

Target

DGKA

Mechanism

DGKA inhibitors

Active Org.

Gilead Sciences, Inc.

Originator Org.

Gilead Sciences, Inc. [+1]

Active Indication

Solid tumor

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ISM-4312A

Target

DGKA

Mechanism

DGKA inhibitors

Active Org.

InSilico Medicine, Inc.

Originator Org.

InSilico Medicine, Inc.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with DGKA

NCT06082960 / RecruitingPhase 1

A Phase 1 Study to Evaluate the Safety and Tolerability of GS-9911 as Monotherapy and in Combination With an Anti-PD-1 Monoclonal Antibody in Adults With Advanced Solid Tumors

The main goal of this first in human (FIH) study is to learn about the safety and dosing of GS-9911 when given alone or in combination with an anti-programmed cell death protein 1 (PD-1) monoclonal antibody in participants with advanced solid tumors.
The primary objectives of this study are to:
Assess the safety and tolerability of GS-9911 as monotherapy and in combination with an anti-PD-1 monoclonal antibody in participants with advanced solid tumors
Identify the maximum tolerated dose (MTD)/maximum administered dose (MAD) and the recommended dose for expansion (RDE) of GS-9911 as monotherapy and in combination with an anti-PD-1 monoclonal antibody in participants with advanced solid tumors

Start Date09 Oct 2023

Sponsor / Collaborator

Gilead Sciences, Inc.

NCT05858164 / RecruitingPhase 1

An Open-label, Phase 1, First-in-human, Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Maximum Tolerated or Administered Dose, Pharmacokinetics, Pharmacodynamics, and Tumor Response Profile of the Diacylglycerol Kinase Alpha Inhibitor (DGKαi) BAY 2862789 in Participants With Advanced Solid Tumors

Researchers are looking for a better way to treat people who have advanced solid tumors including a specific kind of lung cancer (non-small cell lung cancer, NSCLC).
Advanced solid tumors are types of cancer that have spread to nearby tissue, lymph nodes, and/or to distant parts of the body and that are unlikely to be cured or controlled with currently available treatments.
BAY2862789 works by blocking an enzyme in T-cells, thereby activating them. T-cells are a type of immune cell that are known to have an anti-cancer effect.
The main purpose of this first-in-human study is to learn:
how safe different doses of BAY2862789 are,
the degree to which medical problems caused by BAY2862789 can be tolerated (also called tolerability),
what maximum amount (dose) can be given, and
how BAY2862789 moves into, through and out of the body.
To answer this, the researchers will look at:
the number and severity of medical problems participants have after taking BAY2862789 for each dose level. These medical problems are also referred to as adverse events. An adverse event is considered "serious" when it leads to death, puts the participants' lives at risk, requires hospitalization, causes disability, causes a baby being born with medical problems or is otherwise medically important.
the (average) total level of BAY2862789 in the blood (also called AUC) after intake of single and multiple doses.
the (average) highest level of BAY2862789 in the blood (also called Cmax) after intake of single and multiple doses.
Doctors and their team keep track of all medical problems that participants have during the study, even if they do not think the medical problem might be related to the study treatment.
In addition, the researchers want to know if and how the participants' tumors change after taking BAY2862789.
The study will have two parts. The first part, called dose escalation, is done to find the most appropriate dose that can be given in the second part of the study. For this, each participant will receive one of the increasing doses of BAY2862789.
All participants in the second part of the study, called dose expansion, will receive the most appropriate dose identified from the first part of the study, as tablet by mouth. Participants in both parts of the study, will take the study treatment until their tumor gets worse (also known as 'disease progression'), until they have medical problems, until they leave the study, or until the study is terminated.
Each participant will be in the study for several months, including a test (screening) phase of up to 28 days, few months of treatment depending on the participant's benefit, and a follow up phase after the end of treatment. The following approximate numbers of visits to the study site are planned: two during the screening phase, six in the first treatment month, one to three per month in the following periods.
During the study, the study team will:
take blood and urine samples
do physical examinations
check vital signs such as blood pressure, heart rate, body temperature
examine heart health using ECG (electrocardiogram)
check cancer status using CT (computed tomography) or MRI (magnetic resonance imaging) and, if needed, bone scans
take tumor samples (if required)
pregnancy test
The treatment period ends with a visit no later than 7 days after the last BAY2862789 dose. The study doctors and their team will check the participants' health and any changes in cancer about 30 and 90 days after the last dose and every 12 weeks thereafter. This follow-up period ends if the cancer worsens, if a new anti-cancer treatment is started, or until the participant leaves the study. In addition, the study doctors and their team will contact the participant every 12 weeks to learn about the participant's survival. This ends no later than 12 months after the last participant started treatment or by the end of the study, whichever comes first.
If the study participant benefits from treatment, continuation of treatment with BAY2862789 beyond the duration of this study might be possible.

Start Date07 Aug 2023

Sponsor / Collaborator

Bayer AG

100 Clinical Results associated with DGKA

100 Translational Medicine associated with DGKA

0 Patents (Medical) associated with DGKA

213

Literatures (Medical) associated with DGKA

24 Dec 2023·Cancer communications (London, England)

Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma.

Article

Author: Weiren Liu ; Huqiang Wang ; Qianfu Zhao ; Chenyang Tao ; Weifeng Qu ; Yushan Hou ; Run Huang ; Zimei Sun ; Guiqi Zhu ; Xifei Jiang ; Yuan Fang ; Jun Gao ; Xiaoling Wu ; Zhixiang Yang ; Rongyu Ping ; Jiafeng Chen ; Rui Yang ; Tianhao Chu ; Jian Zhou ; Jia Fan ; Zheng Tang ; Dong Yang ; Yinghong Shi

BACKGROUND:

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA.

METHODS:

We performed integrated multiomics analysis in 116 iCCA samples, including whole-exome sequencing, bulk RNA-sequencing and proteome analysis. Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells.

RESULTS:

Three metabolic subtypes (S1-S3) with subtype-specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune-suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT-rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype-specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen-activated protein kinase (MAPK) signaling.

CONCLUSION:

Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.

01 Jul 2023·Biomedicines

Role of Diacylglycerol Kinases in Acute Myeloid Leukemia.

Article

Author: Teresa Gravina ; Chiara Maria Teresa Boggio ; Elisa Gorla ; Luisa Racca ; Silvia Polidoro ; Sara Centonze ; Daniela Ferrante ; Monia Lunghi ; Andrea Graziani ; Davide Corà ; Gianluca Baldanzi

Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including DGKA, DGKD and DGKG, without a precise correlation with specific AML subtypes. In the TGCA database, high DGKA expression negatively correlates with survival, while high DGKG expression is associated with a more favorable prognosis. DGKA and DGKG also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high DGKH expression is correlated with shorter survival. To assess the suitability of DGKs as therapeutic targets, we treated HL-60 and HEL cells with DGK inhibitors and compared cell growth and survival with those of untransformed lymphocytes. We observed a specific sensitivity to R59022 and R59949, two poorly selective inhibitors, which promoted cytotoxicity and cell accumulation in the S phase in both cell lines. Conversely, the DGKA-specific inhibitors CU-3 and AMB639752 showed poor efficacy. These findings underscore the pivotal and isoform-specific involvement of DGKs in AML, offering a promising pathway for the identification of potential therapeutic targets. Notably, the DGKA and DGKH isoforms emerge as relevant players in AML pathogenesis, albeit DGKA inhibition alone seems insufficient to impair AML cell viability.

18 Apr 2023·Journal of bacteriology

Impact of the cAMP-cAMP Receptor Protein Regulatory Complex on Lipopolysaccharide Modifications and Polymyxin B Resistance in Escherichia coli.

Article

Author: Alexandria B Purcell ; Brent W Simpson ; M Stephen Trent

Gram-negative bacteria have a unique cell surface that can be modified to maintain bacterial fitness in diverse environments. A well-defined example is the modification of the lipid A component of lipopolysaccharide (LPS), which promotes resistance to polymyxin antibiotics and antimicrobial peptides. In many organisms, such modifications include the addition of the amine-containing constituents 4-amino-4-deoxy-l-arabinose (l-Ara4N) and phosphoethanolamine (pEtN). Addition of pEtN is catalyzed by EptA, which uses phosphatidylethanolamine (PE) as its substrate donor, resulting in production of diacylglycerol (DAG). DAG is then quickly recycled into glycerophospholipid (GPL) synthesis by the DAG kinase A (DgkA) to produce phosphatidic acid, the major GPL precursor. Previously, we hypothesized that loss of DgkA recycling would be detrimental to the cell when LPS is heavily modified. Instead, we found that DAG accumulation inhibits EptA activity, preventing further degradation of PE, the predominant GPL of the cell. However, DAG inhibition of pEtN addition results in complete loss of polymyxin resistance. Here, we selected for suppressors to find a mechanism of resistance independent of DAG recycling or pEtN modification. Disrupting the gene encoding the adenylate cyclase, cyaA, fully restored antibiotic resistance without restoring DAG recycling or pEtN modification. Supporting this, disruptions of genes that reduce CyaA-derived cAMP formation (e.g., ptsI) or disruption of the cAMP receptor protein, Crp, also restored resistance. We found that loss of the cAMP-CRP regulatory complex was necessary for suppression and that resistance arises from a substantial increase in l-Ara4N-modified LPS, bypassing the need for pEtN modification. IMPORTANCE Gram-negative bacteria can alter the structure of their LPS to promote resistance to cationic antimicrobial peptides, including polymyxin antibiotics. Polymyxins are considered last-resort antibiotics for treatment against multidrug-resistant Gram-negative organisms. Here, we explore how changes in general metabolism and carbon catabolite repression pathways can alter LPS structure and influence polymyxin resistance.

News (Medical) associated with DGKA

20 Dec 2022

·www.biospace.com

Insilico Medicine Nominates Potential First-in-Class Preclinical Candidate with Novel AI-Designed Structure for Novel AI-Discovered Target in Immuno-oncology

New York, Dec. 20, 2022 (GLOBE NEWSWIRE) -- Insilico Medicine (“Insilico”), a clinical-stage end-to-end artificial intelligence (AI)-driven drug discovery company, today announced that the company has nominated ISM4312A as a preclinical candidate targeting DGKA with an AI-identified target and AI-designed structure for immuno-oncology therapeutics. It is another program fully discovered and designed by AI that Insilico has delivered from target identification to preclinical candidate nomination by leveraging its proprietary end-to-end AI platform, Pharma.AI. Immune checkpoint blockade has proven effective in a variety of malignancies, but the response rate of existing therapeutics remains low. The diacylglycerol kinase family (DGKs) is an important player in signal transduction, phosphorylating the membrane lipid, diacylglycerol (DAG), to phosphatidic acid (PA). Research indicates that DGKA mediates T-cell dysfunction during anti-PD-1 therapy, playing a role in the development of resistance to PD-1 blockade. “We are committed to providing novel strategies to improve therapeutic efficacy in immuno-oncology as well as addressing unmet medical needs in the world,” said Feng Ren, PhD, Co-CEO and Chief Scientific Officer of Insilico Medicine. Powered by PandaOmics, the AI-driven target discovery engine of the Pharma.AI platform, scientists designed a project that included bulk RNA sequencing data from 4 datasets alongside 2 single-cell RNA-Seq datasets to identify novel targets for improving therapeutic efficacy. The results show that DGKA inhibitors may overcome anti-PD-1 resistance and expand the responder patient population in cancer immunotherapy. After designing and evaluating a series of compounds in 15 months, scientists nominated ISM4312A as a preclinical candidate and initiated the IND-enabling studies for the program. The preclinical candidate ISM4312A is a potential first-in-class DGKA inhibitor with excellent potency and high selectivity in cancer immunotherapy. The compound enhanced T-cell activity in vitro and showed robust anti-tumor activities with or without anti-PD-1 therapy in vivo. It also exhibited favorable ADME, excellent oral bioavailability, and tolerance. The deeper investigation of the biomarker and combination mechanism is ongoing and Insilico will use the findings to advance a new potential therapeutic strategy in immuno-oncology. "This is the 7th preclinical candidate [PCC] delivered using AI in 2022 alone, bringing the total number of AI-enabled PCCs the company has nominated since 2021 to 9, further validating the strength of our end-to-end Pharma.AI platform," said Alex Zhavoronkov, PhD, Founder and CEO of Insilico Medicine. "Pharma.AI is now used by many pharmaceutical companies to accelerate their pharmaceutical R&D cycles and increase the probabilities of success." Insilico has rapidly developed its portfolio in a variety of disease areas, including fibrosis, inflammation, and cancer. Since 2021, Insilico has nominated 9 preclinical candidates discovered and designed using its AI platform. It also successfully completed a Phase 0 microdose trial and entered a Phase I clinical trial with its first internally developed program for fibrosis. About Insilico Medicine Insilico Medicine, a clinical stage end-to-end artificial intelligence (AI)-driven drug discovery company, is connecting biology, chemistry, and clinical trials analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers, and other modern machine learning techniques for novel target discovery and the generation of novel molecular structures with desired properties. Insilico Medicine is developing breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system diseases, infectious diseases, autoimmune diseases, and aging-related diseases. Website: Contact: media@insilico.com Brita Belli Insilico Medicine 475-225-0843 brita@insilico.com

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DGKA

diacylglycerol kinase alpha

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