Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

Ryu, Hwani; Choi, Hyun Kyung; Kim, Hyo Jeong; Kim, Ah-young; Song, Jie‐Young; Hwang, Sang‐Gu; Kim, Jae Sung; Kim, Da Un; Kim, Eun Ho; Kim, Joon; Ahn, Joon-Woo

doi:10.3390/ijms20194728

Cited by 16 publications

(14 citation statements)

References 39 publications

(44 reference statements)

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“…Here, we showed that 7c inhibited FLT3-STAT5 signaling as well as HR and NHEJ DNA repair genes, probably contributing to the growth inhibition and death of FLT3-ITD + AML cells. These results are consistent with those of our previous study, in which we demonstrated that the inhibition of STAT5 downregulates DNA repair [11]. Previous studies suggested that AML with genomic instability is sensitive to PARP inhibition [10,20].…”

Section: Discussionsupporting

confidence: 94%

“…Inhibition of FLT3-ITD function by quizartinib reduces two major DSB repair activities with homologous recombination (HR) and nonhomologous end-joining (NHEJ). Our previous study supported that quizartinib and the novel FLT3 inhibitor AIU2001 downregulate DNA repair HR and NHEJ genes [10,11]. To investigate whether 7cinduced AML cell death was caused by the inhibition of DNA damage repair pathways, we determined the expression levels of HR and NHEJ genes in Molm-13 and MV4-11 cells.…”

Section: C Suppressed Dna Damage Repairmentioning

confidence: 74%

“…Previous studies suggest that FLT3-ITD + AML cells generate high levels of reactive oxygen species (ROS) that induce DNA damage, mutations, double-strand DNA breaks (DSB), and chromosomal instability, but they can survive owing to enhanced DNA repair activities [9][10][11][12]. Interestingly, FLT3 inhibitors downregulate DNA repair genes of the homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

et al. 2020

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Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD+ induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7; 7c) as candidates for the treatment of AML. The results showed that 7c inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD+ AML cells, increasing apoptosis. The anti-leukemic activity of 7c was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, 7c suppressed the expression of DNA damage repair genes. Combination treatment with 7c and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that 7c is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with 7c and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.

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Section: Discussionsupporting

confidence: 94%

Section: C Suppressed Dna Damage Repairmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

et al. 2020

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“…Cell lysates were prepared by extracting proteins with TNN buffer (40 mM Tris-Cl pH 8.0, 0.2% NP-40, 120 mM NaCl) supplemented with a protease inhibitor cocktail (Thermo Fisher Scientific, Rockford, IL, USA). Western blot analysis was performed as previously described [ 32 ]. Details of the primary antibodies used in this study are provided in the Supplementary Materials and Methods section .…”

Section: Methodsmentioning

confidence: 99%

Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor

Ryu

Nam²,

Kim

et al. 2021

IJMS

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More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/β-catenin activation. Tankyrase (TNKS) mediates the release of active β-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM and DLD-1 cells. The antitumor activities of TI-12403 were confirmed by the viability of the colorectal cancer cells and its lack of visible toxicity in DLD-1 xenograft mouse model. In addition, combined 5-FU and TI-12403 treatment synergistically inhibited proliferation to a greater extent than that in a single drug treatment. Our observations suggest that TI-12403, a novel selective TNKS1 inhibitor, may be a suitable compound for anticancer drug development.

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“…This results in synthetic lethality with PARPi. 100 , 101 In addition, c-MET and EGFR, both similar RTKs, were also found to be hyperactivated in TNBC cells with acquired resistance to PARPi. This is presumably because EGFR and MET heterodimers interact with and phosphorylate the Tyr907 residue of PARP1.…”

Section: Parpi Resistance and Overcoming Strategiesmentioning

confidence: 97%

Recent advancements in PARP inhibitors-based targeted cancer therapy

Zhou

Wang

Mishail

et al. 2020

Precision Clinical Medicine

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Poly(ADP-ribose) polymerase inhibitors (PARPi) are a new class of agents with unparalleled clinical achievement for driving synthetic lethality in BRCA-deficient cancers. Recent FDA approval of PARPi has motivated clinical trials centered around the optimization of PARPi-associated therapies in a variety of BRCA-deficient cancers. This review highlights recent advancements in understanding the molecular mechanisms of PARP ‘trapping’ and synthetic lethality. Particular attention is placed on the potential extension of PARPi therapies from BRCA-deficient patients to populations with other homologous recombination-deficient backgrounds, and common characteristics of PARPi and non-homologous end-joining have been elucidated. The synergistic antitumor effect of combining PARPi with various immune checkpoint blockades has been explored to evaluate the potential of combination therapy in attaining greater therapeutic outcome. This has shed light onto the differing classifications of PARPi as well as the factors that result in altered PARPi activity. Lastly, acquired chemoresistance is a crucial issue for clinical application of PARPi. The molecular mechanisms underlying PARPi resistance and potential overcoming strategies are discussed.

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Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

Cited by 16 publications

References 39 publications

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor

Recent advancements in PARP inhibitors-based targeted cancer therapy

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