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Last update 08 May 2025

DGKA

Last update 08 May 2025

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:15544348, PubMed:2175712). 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:15544348, PubMed:2175712). 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

INCB-177054

Target

DGKA x DGKζ

Mechanism

DGKA inhibitors [+1]

Active Org.

Incyte Corp.

Originator Org.

Incyte Corp.

Active Indication

Advanced Malignant Solid Neoplasm [+2]

Inactive Indication-

Drug Highest PhasePhase 1/2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

BMS-986408

Target

DGKA x DGKζ

Mechanism

DGKA inhibitors [+1]

Active Org.

Bristol Myers Squibb Co.

Originator Org.

Bristol-Myers Squibb Pharmaceuticals Ltd.

Active Indication

Advanced Malignant Solid Neoplasm

Inactive Indication-

Drug Highest PhasePhase 1/2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

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

Clinical Trials associated with DGKA

NCT06873789

/ Not yet recruitingPhase 1/2

A Phase 1/2, Open-Label, Multicenter Study of INCB177054 in Participants With Select Advanced or Metastatic Solid Tumors

This study will be conducted to evaluate INCB177054 given as monotherapy or in combination with retifanlimab in participants with select advanced or metastatic solid Tumors.

Start Date24 Apr 2025

Sponsor / Collaborator

Incyte Corp.

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 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 dose escalation will be done to find the most appropriate dose that can be given. For this, each participant will receive one of the increasing doses of Bay 2862789. More groups might be investigated based on new data that emerges. For this, each participant will receive one of the increasing doses of BAY2862789.
Participants in 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

247

Literatures (Medical) associated with DGKA

01 Jun 2025·Molecular Therapy Oncology

CRISPR-Cas9 knockout of DGKα/ζ improves the anti-tumor activities of TAG-72 CAR-T cells in ovarian cancer

Article

Author: Hudson, Peter J ; Nguyen, Nhu-Y N ; Boyd, Richard L ; Hammett, Maree V ; Pupovac, Aleta ; Shu, Runzhe ; Lee, Jae Young ; Trounson, Alan O ; Evtimov, Vera J ; Kim, Seokjoong ; Zhuang, Junli

High recurrence and chemoresistance in solid tumors, like ovarian cancer, stress the need for new therapies. Chimeric antigen receptor (CAR)-T cells show promise but face challenges due to tumor heterogeneity and immune suppression in the tumor microenvironment (TME). Thus, novel approaches are needed to further enhance the efficacy of CAR-T cell therapies. In T cell therapies, inhibiting checkpoint molecules is crucial for overcoming exhaustion and boosting anti-tumor activity. Additionally, prioritizing safety by engineering cells to target markers absent on normal healthy cells reduces off-target risks. We targeted tumor-associated glycoprotein 72 (TAG-72), an oncofetal antigen highly expressed in adenocarcinomas like ovarian cancer, by engineering TAG-72 CAR-T cells and used CRISPR-Cas9 to knock out the T cell-inhibitory enzymes diacylglycerol kinase (DGK) α and ζ. DGKα/ζ knockout (KO) did not impact CAR-T cell viability or phenotype. These cells selectively killed TAG-72-expressing cancer cells in vitro and ablated established tumors in vivo for up to 100 days, whereas non-deleted control TAG-72 CAR-T cells showed tumor relapse around 40 days. These findings highlight the potential of CRISPR-induced DGKα/ζ KO to enhance CAR-T cell efficacy against solid tumors such as ovarian cancer, offering a promising avenue for improved cancer therapies.

01 Apr 2025·International Journal of Biological Macromolecules

PcoCas12a: A novel CRISPR enzyme from Prevotella copri enhancing TCR-T-cell tumor suppression

Article

Author: Dong, Xuan ; Qi, Chen ; Zhang, Haibo ; Huang, Lei ; Liu, Yi ; Luo, Mei ; Guo, Qiang ; Liu, Longqi ; Zheng, Yue ; Wang, Dan ; Zang, Yupeng ; Shao, Huishan ; Xu, Qumiao ; Shen, Xuechun ; Peng, Jianfang ; Xu, Xun

Genome editing technologies have been widely utilized in cell engineering, demonstrating immense potential in cell and gene therapy. However, an optimal gene-editing enzyme for immune cell editing remains unidentified. In this study, we identified a novel gene editing enzyme, termed CRISPR/PcoCas12a, derived from Prevotella copri, which recognizes a 5'-YYN PAM sequence. We demonstrated that CRISPR/PcoCas12a offers a broader range of editing sites and superior editing efficiency at specific loci compared to AsCas12a. Furthermore, we illustrated its capability to enhance tumor suppression by targeting DGKα in TCR-T cells. DGKα functions as a negative regulator of T cell function, and its knockout significantly boosts the antitumor efficacy of TCR-T cells. The knockout efficiency and tumor suppressor ability of PcoCas12a targeting DGKα were markedly higher than those achieved with AsCas12a. Single-cell sequencing data confirmed that PcoCas12a-mediated DGKα gene knockout improves the tumor suppressive capabilities of T cells by promoting T-cell activation and strengthening immune regulatory responses. These findings establish PcoCas12a as a highly efficient enzyme for T cell editing, indicating its potential application in T-cell therapy.

01 Mar 2025·Cancer Medicine

DGKα Enhances Tumorigenic Activity in Bladder Cancer Patients With Chronic Kidney Disease

Article

Author: Hatayama, Tomoya ; Miyamoto, Shunsuke ; Kitano, Hiroyuki ; Iwane, Kyosuke ; Goto, Keisuke ; Kohada, Yuki ; Goriki, Akihiro ; Takemoto, Kenshiro ; Sekino, Yohei ; Nakano, Yoshinori ; Tasaka, Ryo ; Naito, Miki ; Yamanaka, Ryoken ; Hieda, Keisuke ; Okazaki, Mai ; Tasaka, Shinsaku ; Shikuma, Hiroyuki ; Kobatake, Kohei ; Yukihiro, Kazuma ; Hinata, Nobuyuki

ABSTRACTIntroductionChronic kidney disease (CKD) is a risk factor for bladder cancer (BC) and is reportedly involved in its recurrence and progression. This study aimed to determine the molecular mechanisms underlying the development of BC in patients with CKD.MethodsFirst, we generated the CKD mouse model according to a unilateral two‐stage renal ischemia–reperfusion injury protocol using wild‐type C57BL/6 mice. Second, we conducted a molecular functional analysis of DGKα in BC and investigated the contribution of DGKα to cell invasion, migration, and proliferation activity using human BC cell lines.ResultsAfter confirming elevated serum creatinine levels in mice, the bladder was dissected, and mRNA sequencing of bladder urothelial cells was conducted. Gene expression profiling revealed remarkable upregulation in diacylglycerol kinase alpha (DGKα) level compared to that in control urothelial cells. DGKα‐knockdown cells displayed significantly decreased invasion, migration, and proliferation activity compared to the controls. Next, we conducted a clinical analysis of DGKα in BC patients and performed immunohistochemistry (IHC) on samples from patients treated with radical cystectomy. IHC staining revealed that DGKα‐positive cases had significantly worse recurrence‐free and cancer‐specific survival rates (p = 0.036 and = 0.003, respectively).ConclusionDGKα expression is associated with tumorigenic activity in BC. Therefore, it is speculated that increased expression of DGKα in CKD cases is involved in the malignant potentials in BC. In conclusion, the crucial role of DGKα in BC is suggested, and it may be one of the factors contributing to poor prognosis in BC patients with CKD.

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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