- |||||||||| Review, Journal: An updated patent review of Akt inhibitors (2020-present). (Pubmed Central) - Nov 29, 2023
Futureresearch can be directed toward developing new applications of Aktinhibitors, which may have implications for other diseases beyondcancer. New attempts suggest that targeting allosteric sites may be apotential solution to the problem of isoform selectivity.Furthermore, directly knocking out Akt protein by using the degraderssuggests a promising direction for future development.
- |||||||||| berzosertib (M6620) / EMD Serono, danusertib (PHA-739358) / Nerviano Medical Sciences
Molecular correlates of drug response to guide therapy in triple-negative breast cancer (Hall 2-3) - Nov 4, 2023 - Abstract #SABCS2023SABCS_911;
Furthermore, combining the pan-AK inhibitor danusertib with berzosertib results in synergistic killing of TNBC cells. As a future direction, we are evaluating this combination in vivo utilizing an ethnically diverse patient-derived xenograft library grown in mice to evaluate this novel combination in a mock clinical trial and to identify molecular correlates of response and resistance that could be used to guide future human trials.
- |||||||||| Hypoxia-inducible factor (HIF-1) orchestrates adenosine metabolism to promote liver cancer development (Poster and Exhibition Hall) - Jun 13, 2023 - Abstract #EACR2023EACR_975;
Knockout of ADK in vivo skewed intratumoral immune cells to pro-tumorigenic and promoted tumor progression. Therapeutically, combination treatment of adenosine receptor antagonists and anti-PD-1 prolonged survival of HCC-bearing mice.ConclusionWe illustrated the significance of the dual role of hypoxia in creating an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that might synergize with ICIs in HCC.
- |||||||||| Journal: Role of Adenosine Kinase in Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities. (Pubmed Central) - Oct 18, 2022
Moreover, the selective AAR antagonist, MRS1523, prevents the ability of ABT702 to block SEW2871 and IL-1β-induced allodynia, implicating AAR signaling in the beneficial effects exerted by ABT702. Our findings provide novel mechanistic insight into how S1PR1 signaling in the spinal cord produces hypersensitivity through IL1-β and ADK activation.
- |||||||||| Adenosine kinase isoforms in cellular proliferation (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_8110;
Our findings provide novel mechanistic insight into how S1PR1 signaling in the spinal cord produces hypersensitivity through IL1-β and ADK activation. Together, we established an in vitro cellular platform for the development of ADK inhibitors as a potential therapeutic antitumor application.
- |||||||||| decitabine / Generic mfg.
Review, Journal: Adenosine Kinase on Deoxyribonucleic Acid Methylation: Adenosine Receptor-Independent Pathway in Cancer Therapy. (Pubmed Central) - Jun 22, 2022
Targeting DNA methylation of cancer-related genes is a promising therapeutic strategy; drugs like 5-Aza-2'-deoxycytidine (5-AZA-CdR, decitabine) effectively reverse DNA methylation and cancer cell growth...Most recently, an adenosine metabolic clearance enzyme, adenosine kinase (ADK), has been shown to influence methylation on tumor suppressor genes and tumor development and progression. This review article focuses on recent updates on ADK and its two isoforms, and its actions in adenosine receptor-independent pathways, including methylation modification and epigenetic changes in cancer pathology.
- |||||||||| Journal: Synthesis of Sugar and Nucleoside Analogs and Evaluation of Their Anticancer and Analgesic Potentials. (Pubmed Central) - Jun 19, 2022
Cytotoxic compound 6 demonstrated strong docking with cancer drug targets human cytidine deaminase, proto-oncogene tyrosine-protein kinase Src, human thymidine kinase 1, human thymidylate synthase, and human adenosine deaminase 2. This is the first ever reporting of the synthesis and analgesic property of compound 8 and the cytotoxic potential of compound 6.
- |||||||||| Niagen (nicotinamide riboside) / ChromaDex
Journal: Dihydronicotinamide Riboside Is a Potent NAD Precursor Promoting a Pro-Inflammatory Phenotype in Macrophages. (Pubmed Central) - May 6, 2022
Interestingly, the IKK inhibitor, BMS-345541, blocked the mRNA expression of several enzymes and transporters involved in the NAD boosting effect of NRH, indicating that IKK is also a regulator of NAD metabolism. In conclusion, NAD precursors such as NRH may be important tools to understand the role of NAD and NADH metabolism in the inflammatory process of other immune cells, and to reprogram immune cells to a pro-inflammatory phenotype, such as the M2 to M1 switch in macrophage reprogramming, in the cancer microenvironment.
- |||||||||| Journal: Overview of Protein Kinase B Enzyme:a Potential Target for breast and Prostate Cancer. (Pubmed Central) - Apr 1, 2022
To date, limited numbers of AKT inhibitors have been identified, and none are strongly selective for AKT isoforms. In this regard, we discussed the current insight of AKT inhibitors in drug development, protein structure, and mechanism as well as the role of AKT in the development of drug targets for breast cancer and prostate cancer.
- |||||||||| Aurora kinase is synthetic lethal with APC loss of function in engineered human colon organoid models (Section 1) - Mar 9, 2022 - Abstract #AACR2022AACR_4306;
Despite these encouraging results indicating therapeutic opportunity in early adenoma disease, on-target genotoxicity was observed in vitro through increases in micronuclei at pharmacologic doses. Therefore, although there is a high unmet need in FAP for therapeutic options, potential genotoxicity associated with AK inhibitor treatments may limit utility as an intervention strategy.
- |||||||||| fludarabine IV / Generic mfg.
Preclinical, Journal: 5-Iodotubercidin inhibits SARS-CoV-2 RNA synthesis. (Pubmed Central) - Feb 24, 2022
Among these four compounds, 5-Iodotubercidin exhibited the strongest inhibition upon SARS-CoV-2 RdRp, and was resistant to viral exoribonuclease activity, thus presenting the best antiviral activity against coronavirus from a different genus. Further study showed that the RdRp inhibitory activity of 5-Iodotubercidin is closely related to its capacity to inhibit adenosine kinase (ADK).
- |||||||||| methotrexate / Generic mfg., ibuprofen / Generic mfg.
Journal: Influence of NSAIDs and methotrexate on CD73 expression and glioma cell growth. (Pubmed Central) - Jan 29, 2022
In summary, only MTX increased the expression of CD73 in GBM cells decreasing cells viability by mechanisms independent of the adenosinergic system. Further studies are needed to understand the role of MTX in the GBM microenvironment.
- |||||||||| Exploration of protein conformational space with variational autoencoder (In-Person Room (Virtual Room)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_10191;
Moreover, we showed that the learned latent space can be used to generate unsampled protein conformations. Additional simulations starting from these generated conformations can capture biological-relevant transitions among conformational states with significantly less sampling.
- |||||||||| memantine / Generic mfg.
Journal: A chemical genomics-aggrephagy integrated method studying functional analysis of autophagy inducers. (Pubmed Central) - Jan 18, 2022
These results, with the combined approach, suggested that autophagy-activating small molecules may improve proteinopathies by eliminating nonfunctional protein aggregates. ADK: adenosine kinase; AMPK: AMP-activated protein kinase; ATF4: activating transcription factor 4; BECN1: beclin-1; DDIT3/CHOP: DNA damage inducible transcript 3; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2S1/eIF2α: eukaryotic translation initiation factor 2 subunit alpha; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FDA: Food and Drug Administration; GSH: glutathione; HD: Huntington disease; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; HTT: huntingtin; JAK: Janus kinase, MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MAP2K/MEK: mitogen-activated protein kinase kinase; MAP3K8/Tpl2: mitogen-activated protein kinase kinase kinase 8; MAPK: mitogen-activated protein kinase; MPP: 1-methyl-4-phenylpyridinium; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; NAC: N-acetylcysteine; NGF: nerve growth factor 2; NMDA: N-methyl-D-aspartate; PCA: principal component analysis; PD: Parkinson disease; PDA: pancreatic ductal adenocarcinoma; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PMA: phorbol 12-myristate 13-acetate; PRKC/PKC: protein kinase C; ROCK: Rho-associated coiled-coil protein kinase; RR: ribonucleotide reductase; SIGMAR1: sigma non-opioid intracellular receptor 1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TFEB: Transcription factor EB; TGFB/TGF-β: Transforming growth factor beta; ULK1: unc-51 like autophagy activating kinase 1; XBP1: X-box binding protein 1.
- |||||||||| Journal: Adenosine Kinase: An Epigenetic Modulator in Development and Disease. (Pubmed Central) - Jan 18, 2022
This review will provide a comprehensive overview of ADK-associated changes in DNA methylation in developmental, as well as in pathological conditions including brain injury, epilepsy, cancer, and diabetes. Challenges in investigating the epigenetic role of ADK for therapeutic gains are briefly discussed.
- |||||||||| Adenosine-A2A receptor signaling plays a crucial role in sudden unexpected death in epilepsy (SUDEP) () - Dec 12, 2021 - Abstract #AES2021AES_574;
Taken together, providing an example of how low-level brain somatic mutation can change the entire brain activity, this study showed that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non-cell autonomous hyperexcitability of nearby non-mutated neurons. Together, we revealed a crucial role for NTS A2AR in SUDEP pathophysiology suggesting A2AR as a potential therapeutic target for SUDEP risk prevention.
- |||||||||| Journal: Recent Advances in the Discovery of GSK-3 Inhibitors from Synthetic Origin in the Treatment of Neurological Disorders. (Pubmed Central) - Dec 1, 2021
The molecules were evaluated against the effectivity of GSK-3, human adenosine kinase, cyclin dependent kinase, and phosphodiesterase-4 along with tail suspension test, forced swim test, percent neuronal survival and other cognitive behaviour. The observations confirmed the remarkable effects of the synthesized molecules to conquer Alzheimer, Parkinson's depression, psychosis and other forms of neurological disorders.
- |||||||||| Journal: Proteome Changes in Stem Tissues of Sunflower Lines Inoculated with Culture Filtrate of Sclerotinia sclerotiorum. (Pubmed Central) - Nov 29, 2021
Moreover, the expression of pyrroline-5-carboxylate reductase, involved in proline biosynthesis, was significantly changed in both sunflower lines in response to pathogen culture filtrate. Proteins which were only up-regulated in the partially resistant lines might have a significant role in mediating the defense against Sclerotinia and could be considered for enhancing resistance against this devastating pathogen.
- |||||||||| Journal: Non-cell autonomous epileptogenesis in focal cortical dysplasia. (Pubmed Central) - Nov 10, 2021
Hence, the results from our study suggest that vicine was shown to be toxic that suppresses the ADK activity to undergo pathological conditions in the neuronal junctions to lead epilepsy. No abstract available
- |||||||||| buparlisib (BKM120) / Novartis, Adlai Nortye
Targeting Metabolic Vulnerabilities in Primary Effusion Lymphoma Using the Novel Nucleoside Analog 6-Eti (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_2747;
Our data indicates that ADK KO cells have undergone metabolic reprogramming to upregulate de novo pyrimidine biosynthesis and p70S6K signaling. Moreover, we found that 6-ETI synergizes with the pan PI3K inhibitor BKM120 highlighting nucleotide metabolism and PI3K/mTOR signaling as key therapeutic vulnerabilities targeted by this novel nucleoside analog.
- |||||||||| Journal: Adenosine Triggers Larval Settlement and Metamorphosis in the Mussel Mytilopsis sallei through the ADK-AMPK-FoxO Pathway. (Pubmed Central) - Nov 4, 2021
The results of transcriptomic analyses, pharmacological assays, temporal and spatial gene expression analyses, and siRNA interference, suggest that ATP-dependent phosphorylation of adenosine catalyzed by ADK activates the downstream AMPK-FoxO signaling pathway, inducing larval settlement and metamorphosis in M. sallei. This study not only reveals the role of the ADK-AMPK-FoxO pathway in larval settlement and metamorphosis of marine invertebrates but it also deepens our understanding of the functions and evolution of adenosine signaling, a process that is widespread in biology and important in medicine.
- |||||||||| Journal: Inhibition of adenosine kinase attenuates myocardial ischaemia/reperfusion injury. (Pubmed Central) - Sep 25, 2021
X-linked inhibitor of apoptosis protein (XIAP), which is phosphorylated and stabilized via the adenosine receptors A2B and A1/Akt pathways, should play a central role in the effects of ADK inhibition on cell apoptosis and necroptosis. These data suggest that ADK plays an important role in myocardial I/R injury by regulating cell apoptosis and necroptosis.
- |||||||||| Review, Journal: Adenosine Kinase: A Key Regulator of Purinergic Physiology. (Pubmed Central) - Sep 16, 2021
However, clinical development of early ADK inhibitors was stopped due to apparent mechanistic toxicity and the lack of suitable translational markers. New insights regarding the potential role of the nuclear ADK isoform (ADK-Long) in the epigenetic modulation of maladaptive DNA methylation offers the possibility of identifying novel ADK-isoform selective inhibitors and new interventional strategies that are independent of ADO receptor activation.
- |||||||||| Journal: High-Throughput Screening Assays for Cancer Immunotherapy Targets: Ectonucleotidases CD39 and CD73. (Pubmed Central) - Jul 18, 2021
The Transcreener ADP2 Assay was used to screen 1600 compounds from the ChemBridge diversity library for CD73 inhibitors and identified 14 potential candidates. HTS-compatible assays for ectonucleotidase activity may allow identification of purinergic signaling pathway inhibitors important for tumor-specific immune responses during tumor pathogenesis.
- |||||||||| Preclinical, Journal: Adenosine inhibits cell proliferation differently in human astrocytes and in glioblastoma cell lines. (Pubmed Central) - Jul 14, 2021
Adenosine alone did not induce cell death, assessed by LDH release, both in HA and GBM cells, but potentiated cytotoxic effect of homocysteine in HA and in U87MG and U373MG cells. Results show a strong attenuation of adenosine anti-proliferative effect in GBM cells compared to HA, probably resulting from increased adenosine elimination by ADK, suggesting a proliferative-prone adaptation of tumour cells to increased adenosine levels.
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