A Small Molecule Inhibitor, OGP46, Is Effective against Imatinib-Resistant BCR-ABL Mutations via the BCR-ABL/JAK-STAT Pathway

Wei, Liuya; Yang, Yang; Gupta, Pranav; Wang, Aihong; Zhao, Min; Zhao, Yao; Qu, Mei; Yu, Ke; Liu, Ying; Liu, Hong‐Min; Xu, Xin; Sun, Ying; Chen, Zhe‐Sheng; Hu, Zhenbo

doi:10.1016/j.omto.2020.06.008

Cited by 12 publications

(22 citation statements)

References 40 publications

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“…Oridonin was a component of the Rabdosia rubescens , a traditional Chinese Medicine, which was effective on 31 cases of primary liver cancer by the clinical observation. As described in our previous work ( Wei et al, 2020 ), OGP46 has been shown to induce cell differentiation and inhibit the cell proliferation of chronic myeloid leukemia (CML) cell lines expressing native BCR-ABL and mutant BCR-ABL, including T315I through the BCR-ABL/JAKSTAT pathway by depleting the BCR-ABL oncogene. Moreover, OGP46 was less toxic to normal blood mononuclear cells.…”

Section: Introductionmentioning

confidence: 82%

“…Our previous study had found that OGP46 exhibited potent activity against CML cell lines by inducing cell differentiation ( Wei et al, 2020 ). In this study, we discovered that OGP46 induced cell-cycle arrest at the G1/G0 phase and caused inhibition of cell proliferation by inducing cell differentiation in HL-60, NB4, and Kasumi-1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…After OGP46 incubation for 48 h, cells were collected for RNA extraction. As described in our previous work ( Wei et al, 2020 ), oligo (dT) selection was used to enrich poly (A) mRNA from total RNA. The cDNA libraries were prepared and then sequenced on an Illumina genome analyzer.…”

Section: Methodsmentioning

confidence: 99%

“…Western blotting was carried out as described ( Wei et al, 2020 ) by using the indicated antibodies.…”

Section: Methodsmentioning

confidence: 99%

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OGP46 Induces Differentiation of Acute Myeloid Leukemia Cells via Different Optimal Signaling Pathways

Zhao

Wang

et al. 2021

Front. Cell Dev. Biol.

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Acute myelogenous leukemia (AML) is characterized by blockage of cell differentiation leading to the accumulation of immature cells, which is the most prevalent form of acute leukemia in adults. It is well known that all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are the preferred drugs for acute promyelocytic leukemia (APL). However, they can lead to irreversible resistance which may be responsible for clinical failure after complete remission (CR). Moreover, the differentiation therapy of ATRA-based treatment has not been effective against AML with t(8;21) translocation. Here we aimed to identify the differentiation effect of OGP46 on AML cell lines (HL-60, NB4, and Kasumi-1) and explore its possible mechanisms. We found that OGP46 has significant inhibitory activity against these cells by triggering cell differentiation with cell-cycle exit at G1/G0 and inhibited the colony-formation capacity of the AML cells. It was shown that OGP46 induced the differentiation of NB4 cells via the transcriptional misregulation in cancer signaling pathway by PML-RARα depletion, while it was attributed to the hematopoietic cell lineage and phagosome pathway in Kasumi-1 cells, which are all critical pathways in cell differentiation. These results highlight that OGP46 is an active agent not only in the APL cell line NB4 but also in AML-M2 cell lines, especially Kasumi-1 with t(8;21) translocation. Therefore, OGP46 may be a potential compound for surmounting the differentiation blockage in AML.

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Section: Introductionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Western blotting was carried out as described ( Wei et al, 2020 ) by using the indicated antibodies.…”

Section: Methodsmentioning

confidence: 99%

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OGP46 Induces Differentiation of Acute Myeloid Leukemia Cells via Different Optimal Signaling Pathways

Zhao

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…mRNA-Sequencing (mRNA-seq) was performed for MOLM-13 and THP-1 cells. As described in a previous work [12], after incubating with JOA for 48 h, cells were collected for RNA extraction. Sequencing libraries were prepared and then sequenced using 150 bp pair-end strategies with an Illumina HiSeq X10 instrument (Annoroad Genomics, Beijing, China).…”

Section: Mrna-sequencing Analysismentioning

confidence: 99%

Jiyuan Oridonin A Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cells With MLL Rearrangements via Multiple Signaling Pathways

Duan

Zhao

et al. 2021

Front. Oncol.

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Differentiation therapy with all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), has been extremely successful in inducing clinical remission in APL patients. However, the differentiation therapy of ATRA-based treatment has not been effective in other subtypes of AML. In this study, we evaluated a small molecule of ent-kaurene diterpenoid, Jiyuan oridonin A (JOA), on the differentiation blockade in AML cells with the mixed lineage leukemia (MLL) gene rearrangements (MLLr) in MV4-11, MOLM-13 and THP-1 cells. We found that JOA could significantly inhibit the proliferation of MOLM-13, MV4-11 and THP-1 cells. Moreover, JOA promoted cell differentiation coupled with cell-cycle exit at G0/G1 and inhibited the colony- forming capacity of these cells. We showed that the anti-proliferative effect of JOA attributed to cell differentiation is most likely through the martens tretinoin response up pathway in the MOLM-13 cell line, and the hematopoietic cell lineage pathway by the inhibition of c-KIT expression and cell adhesion pathway in the THP-1 cell line. Our findings suggest that JOA could be a novel therapeutic agent against human MLLr acute myeloid leukemia.

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Development of covalent inhibitors: Principle, design, and application in cancer

Zheng,

Li,

et al. 2023

MedComm – Oncology

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Covalent inhibitors have been a rapidly growing field in drug discovery due to their therapeutic potential and unique advantages in cancer therapy. As opposed to noncovalent inhibitory drugs, covalent inhibitors reversibly or irreversibly modify proximal nucleophilic amino acid residues on proteins, aiming to selectively recognize and bind to protein targets and addressing some of the challenges faced by noncovalent drugs. Most successful targeted covalent inhibitors depend primarily on binding‐site cysteine residues, but this has limitations for certain protein targets that lack targetable cysteine residues. Recently, the rational design of covalent inhibitors or covalent probes targeting other nucleophilic residues, such as lysine, tyrosine, serine, has turned out to be another promising strategy for cancer therapy. Thus, the development of novel strategies to extend the scope of covalent binding and improve the binding properties is required. This review gives a summary of the development of covalent inhibitors targeting noncysteine from different aspects, including target identification, structure–activity relationships, drug discovery strategies, and binding properties, in the hope of providing a scientific reference for future covalent drug discovery as a means of expanding research in cancer therapy.

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A Small Molecule Inhibitor, OGP46, Is Effective against Imatinib-Resistant BCR-ABL Mutations via the BCR-ABL/JAK-STAT Pathway

Cited by 12 publications

References 40 publications

OGP46 Induces Differentiation of Acute Myeloid Leukemia Cells via Different Optimal Signaling Pathways

OGP46 Induces Differentiation of Acute Myeloid Leukemia Cells via Different Optimal Signaling Pathways

Jiyuan Oridonin A Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cells With MLL Rearrangements via Multiple Signaling Pathways

Development of covalent inhibitors: Principle, design, and application in cancer

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