Development and preclinical pharmacology of a novel dCK inhibitor, DI-87

Poddar, Soumya; Capparelli, Edmund V.; Rosser, Ethan W.; Gipson, Raymond M.; Liu, Wei; Le, Thuc; Jung, Michael E.; Radu, Caius G.; Nikanjam, Mina

doi:10.1016/j.bcp.2019.113742

Cited by 11 publications

(16 citation statements)

References 19 publications

(23 reference statements)

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“…Pharmacological PNP inhibition blocks dG catabolism in both stromal and HSPC cell compartments, thereby mimicking dG accumulation in thymi from PNPi-treated mice ( Supplemental Figure 1B ). To investigate whether dCK plays a role in mediating the effects of PNPi and dG, we used a highly selective and potent dCK inhibitor developed by our group [( R )-DI-87; dCKi] ( 15 ). After 5 weeks of culture, most T cell precursors in control ATOs progressed from the CD4/CD8 double-negative (DN) to the CD4/CD8 double-positive (DP) stage ( Figure 1B ).…”

Section: Resultsmentioning

confidence: 99%

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity

Abt¹,

Rashid²,

Le³

et al. 2022

Journal of Clinical Investigation

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Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.

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Section: Resultsmentioning

confidence: 99%

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity

Abt¹,

Rashid²,

Le³

et al. 2022

Journal of Clinical Investigation

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“…DCK is a rate-limiting enzyme of the salvage pathway, which is involved in the synthesis of deoxyribonucleotide triphosphates (dNTPs); dNTPs are essential for DNA replication, repair, and tumor growth. Therefore, inhibiting the activity of DCK may inhibit tumor growth [20]. However, this gene is also associated with gemcitabine resistance [21,22].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide CRISPR Screening Identifies DCK and CCNL1 as Genes That Contribute to Gemcitabine Resistance in Pancreatic Cancer

Yang

Liu

et al. 2022

Cancers

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Pancreatic cancer is one of the most lethal cancers. Due to the difficulty of early diagnosis, most patients are diagnosed with metastasis or advanced-stage cancer, limiting the possibility of surgical treatment. Therefore, chemotherapy is applied to improve patient outcomes, and gemcitabine has been the primary chemotherapy drug for pancreatic cancer for over a decade. However, drug resistance poses a significant challenge to the efficacy of chemotherapy. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) gene-editing system is a powerful tool, and researchers have developed CRISPR/Cas9 library screening as a means to identify the genes associated with specific phenotype changes. We performed genome-wide CRISPR/Cas9 knockout screening in the mouse pancreatic cancer cell line TB32047 with gemcitabine treatment and identified deoxycytidine kinase (DCK) and cyclin L1 (CCNL1) as the top hits. We knocked out DCK and CCNL1 in the TB32047 and PANC1 cell lines and confirmed that the loss of DCK or CCNL1 enhanced gemcitabine resistance in pancreatic cells. Many researchers have addressed the mechanism of DCK-related gemcitabine resistance; however, no study has focused on CCNL1 and gemcitabine resistance. Therefore, we explored the mechanism of CCNL1-related gemcitabine resistance and found that the loss of CCNL1 activates the ERK/AKT/STAT3 survival pathway, causing cell resistance to gemcitabine treatment.

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“…Even though DI-39 showed promising results as a single agent and more prominently as combination therapy with other inhibitors of pyrimidine de novo synthesis in ALL cancer cells and mouse models, DI-39 has limited solubility and metabolic stability due to a short half-life in vivo leading to the development of additional dCK inhibitors with DI-87 being the most promising candidate ( Figure 2 B,D) [ 73 , 74 ]. The newly developed small molecule DI-87 showed promising pharmacological effects in vitro as well as in vivo ALL models [ 73 ].…”

Section: Pyrimidine Salvage As Target In Cancer Therapymentioning

confidence: 99%

Re-Discovery of Pyrimidine Salvage as Target in Cancer Therapy

Walter

Herr

2022

Cells

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Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the de novo pathway synthesizes nucleotides from amino acids and glucose, the salvage pathway recovers nucleosides or bases formed during DNA or RNA degradation. In contrast to high proliferating non-malignant cells, which are highly dependent on the de novo synthesis, cancer cells can switch to the nucleoside salvage pathways to maintain efficient DNA replication. Pyrimidine de novo synthesis remains the target of interest in cancer therapy and several inhibitors showed promising results in cancer cells and in vivo models. In the 1980s and 1990s, poor responses were however observed in clinical trials with several of the currently existing pyrimidine synthesis inhibitors. To overcome the observed limitations in clinical trials, targeting pyrimidine salvage alone or in combination with pyrimidine de novo inhibitors was suggested. Even though this approach showed initially promising results, it received fresh attention only recently. Here we discuss the re-discovery of targeting pyrimidine salvage pathways for DNA replication alone or in combination with inhibitors of pyrimidine de novo synthesis to overcome limitations of commonly used antimetabolites in various preclinical cancer models and clinical trials. We also highlight newly emerged targets in pyrimidine synthesis as well as pyrimidine salvage as a promising target in immunotherapy.

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Development and preclinical pharmacology of a novel dCK inhibitor, DI-87

Cited by 11 publications

References 19 publications

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity

Genome-Wide CRISPR Screening Identifies DCK and CCNL1 as Genes That Contribute to Gemcitabine Resistance in Pancreatic Cancer

Re-Discovery of Pyrimidine Salvage as Target in Cancer Therapy

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