Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2

Serafim, Ricardo Augusto Massarico; Gama, F.; Dutra, Luiz Antônio; Reis, C.V. dos; Vasconcelos, Stanley N. S.; Santiago, André da Silva; Takarada, Jéssica; Pillo, Fúlvia Di; Azevedo, Hátylas; Mascarello, Alessandra; Elkins, J.M.; Massirer, Katlin B.; Gileadi, O.; Guimarães, Cristiano Ruch Werneck; Counago, R.M.

doi:10.1021/acsmedchemlett.9b00082

Cited by 21 publications

(22 citation statements)

References 26 publications

(50 reference statements)

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“…VRK1 depletion led to a significant reduction in the dose needed to achieve a similar effect (Campillo- Lazo, 2018, 2019;Garcia-Gonzalez et al, 2020). Recently, a pyrimidine-based inhibitor has shown high affinity and specificity for the VRK1 kinase (Serafim et al, 2019), which can be a candidate for future drug development.…”

Section: Discussionmentioning

confidence: 99%

VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells

Navarro-Carrasco

Lazo

2021

Front. Cell Dev. Biol.

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BackgroundGlioblastomas treated with temozolomide frequently develop resistance to pharmacological treatments. Therefore, there is a need to find alternative drug targets to reduce treatment resistance based on tumor dependencies. A possibility is to target simultaneously two proteins from different DNA-damage repair pathways to facilitate tumor cell death. Therefore, we tested whether targeting the human chromatin kinase VRK1 by RNA interference can identify this protein as a novel molecular target to reduce the dependence on temozolomide in combination with olaparib, based on synthetic lethality.Materials and MethodsDepletion of VRK1, an enzyme that regulates chromatin dynamic reorganization and facilitates resistance to DNA damage, was performed in glioblastoma cells treated with temozolomide, an alkylating agent used for GBM treatment; and olaparib, an inhibitor of PARP-1, used as sensitizer. Two genetically different human glioblastoma cell lines, LN-18 and LN-229, were used for these experiments. The effect on the DNA-damage response was followed by determination of sequential steps in this process: H4K16ac, γH2AX, H4K20me2, and 53BP1.ResultsThe combination of temozolomide and olaparib increased DNA damage detected by labeling free DNA ends, and chromatin relaxation detected by H4K16ac. The combination of both drugs, at lower doses, resulted in an increase in the DNA damage response detected by the formation of γH2AX and 53BP1 foci. VRK1 depletion did not prevent the generation of DNA damage in TUNEL assays, but significantly impaired the DNA damage response induced by temozolomide and olaparib, and mediated by γH2AX, H4K20me2, and 53BP1. The combination of these drugs in VRK1 depleted cells resulted in an increase of glioblastoma cell death detected by annexin V and the processing of PARP-1 and caspase-3.ConclusionDepletion of the chromatin kinase VRK1 promotes tumor cell death at lower doses of a combination of temozolomide and olaparib treatments, and can be a novel alternative target for therapies based on synthetic lethality.

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Section: Discussionmentioning

confidence: 99%

VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells

Navarro-Carrasco

Lazo

2021

Front. Cell Dev. Biol.

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“…However, studies have noted which inhibitors VRK family proteins are most sensitive to, which is useful in preclinical studies since high drug concentrations are necessary ( 58 ). More importantly, work in 2019 began the development of aminopyridine-based compounds to specifically inhibit VRK1 and VRK2 ( 72 ). Fortunately, the unique structure of these kinases means future inhibitors will be specific to VRK family proteins, with little unintended binding to other kinases, making VRK2 a very attractive drug target.…”

Section: Vrk2mentioning

confidence: 99%

Combination Approaches to Target PD-1 Signaling in Cancer

2022

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Cancer remains the second leading cause of death in the US, accounting for 25% of all deaths nationwide. Immunotherapy techniques bolster the immune cells’ ability to target malignant cancer cells and have brought immense improvements in the field of cancer treatments. One important inhibitory protein in T cells, programmed cell death protein 1 (PD-1), has become an invaluable target for cancer immunotherapy. While anti-PD-1 antibody therapy is extremely successful in some patients, in others it fails or even causes further complications, including cancer hyper-progression and immune-related adverse events. Along with countless translational studies of the PD-1 signaling pathway, there are currently close to 5,000 clinical trials for antibodies against PD-1 and its ligand, PD-L1, around 80% of which investigate combinations with other therapies. Nevertheless, more work is needed to better understand the PD-1 signaling pathway and to facilitate new and improved evidence-based combination strategies. In this work, we consolidate recent discoveries of PD-1 signaling mediators and their therapeutic potential in combination with anti-PD-1/PD-L1 agents. We focus on the phosphatases SHP2 and PTPN2; the kinases ITK, VRK2, GSK-3, and CDK4/6; and the signaling adaptor protein PAG. We discuss their biology both in cancer cells and T cells, with a focus on their role in relation to PD-1 to determine their potential in therapeutic combinations. The literature discussed here was obtained from a search of the published literature and ClinicalTrials.gov with the following key terms: checkpoint inhibition, cancer immunotherapy, PD-1, PD-L1, SHP2, PTPN2, ITK, VRK2, CDK4/6, GSK-3, and PAG. Together, we find that all of these proteins are logical and promising targets for combination therapy, and that with a deeper mechanistic understanding they have potential to improve the response rate and decrease adverse events when thoughtfully used in combination with checkpoint inhibitors.

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“…The structure of the VRK1 protein catalytic site predicts that this kinase not promiscuous and its inhibitors are likely to be highly specific [ 163 , 164 ]. Recently, some VRK1 specific inhibitors, based on an aminopyridine scaffold, are functional at pharmacological concentrations that inhibit tumor cell growth [ 165 ] and effect similar to VRK1 depletion [ 159 ], however, still need testing to determine their therapeutic potential.…”

Section: Targeting Nuclear Kinases Associated With Chromatin Remodeli...mentioning

confidence: 99%

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Lazo

2022

Cancers

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Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.

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Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2

Cited by 21 publications

References 26 publications

VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells

VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells

Combination Approaches to Target PD-1 Signaling in Cancer

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

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