XRK3F2
目录号 : GC34330
XRK3F2 is an inhibitor of the p62-ZZ domain that blunts MM-induced Runx2 suppression in vitro, and induces new bone formation and remodeling in the presence of tumor in vivo.
Cas No.:2375193-43-2
Sample solution is provided at 25 µL, 10mM.
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XRK3F2 is an inhibitor of the p62-ZZ domain that blunts MM-induced Runx2 suppression in vitro, and induces new bone formation and remodeling in the presence of tumor in vivo.
XRK3F2 blocks TNFα and MM (Multiple myeloma) activation of downstream signaling from the p62-signaling hub. In addition, XRK3F2 also directly decreases osteoclast formation. It directly inhibits cell growth of primary CD138+ MM cells and human MM cell lines in vitro, without negatively affecting the growth of BMSC[1]. XRK3F2 has no effect on non-MM bearing bone. XRK3F2 blocks TNFα but not IL-1β stimulated NFκB phosphorylation in MM patient BMSC and inhibits IκBα degradation by interfering with p-IκBα activation in MM cells treated with TNFα. XRK3F2 also significantly inhibits TNFα-enhanced VCAM-1, IL-6, and RANKL expression by BMSCs from MM patients compared to vehicle. XRK3F2 directly activates caspases 3, 7, and 9 in MM cells and decreases NFκB signaling in MM results in the aggregation of caspase 8 and its downstream effector caspases. Thus, high concentrations of XRK3F2 induce apoptosis in MM cells[2].
In vivo, XRK3F2 induces new bone formation and remodeling in the presence of tumor. The t1/2 of XRK3F2 in mice is 10.3 hours. XRK3F2 induces dramatic, local new bone formation in bones bearing MM in vivo but does not induce new bone formation in bones from the same animals that are not directly inoculated with MM cells. The results demonstrate that XRK3F2 alters the effect of MM on bone[2].
[1] Adamik J, et al. Front Endocrinol (Lausanne). 2018, 9:344. [2] Teramachi J, et al. Leukemia. 2016, 30(2):390-8.
| Cas No. | 2375193-43-2 | SDF | |
| Canonical SMILES | FC(C=C1)=CC=C1COC2=C(OCC3=CC=C(F)C=C3)C=C(CNCCO)C=C2.Cl | ||
| 分子式 | C23H24ClF2NO3 | 分子量 | 435.89 |
| 溶解度 | DMSO : 150 mg/mL (344.12 mM);Water : 0.91 mg/mL (2.09 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2942 mL | 11.4708 mL | 22.9416 mL |
| 5 mM | 0.4588 mL | 2.2942 mL | 4.5883 mL |
| 10 mM | 0.2294 mL | 1.1471 mL | 2.2942 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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XRK3F2 Inhibition of p62-ZZ Domain Signaling Rescues Myeloma-Induced GFI1-Driven Epigenetic Repression of the Runx2 Gene in Pre-osteoblasts to Overcome Differentiation Suppression
Front Endocrinol (Lausanne) 2018 Jun 29;9:344.PMID:30008697DOI:10.3389/fendo.2018.00344.
Multiple myeloma bone disease (MMBD) is characterized by non-healing lytic bone lesions that persist even after a patient has achieved a hematologic remission. We previously reported that p62 (sequestosome-1) in bone marrow stromal cells (BMSC) is critical for the formation of MM-induced signaling complexes that mediate OB suppression. Importantly, XRK3F2, an inhibitor of the p62-ZZ domain, blunted MM-induced Runx2 suppression in vitro, and induced new bone formation and remodeling in the presence of tumor in vivo. Additionally, we reported that MM cells induce the formation of repressive chromatin on the Runx2 gene in BMSC via direct binding of the transcriptional repressor GFI1, which recruits the histone modifiers, histone deacetylase 1 (HDAC1) and Enhancer of zeste homolog 2 (EZH2). In this study we investigated the mechanism by which blocking p62-ZZ domain-dependent signaling prevents MM-induced suppression of Runx2 in BMSC. XRK3F2 prevented MM-induced upregulation of Gfi1 and repression of the Runx2 gene when present in MM-preOB co-cultures. We also show that p62-ZZ-domain blocking by XRK3F2 also prevented MM conditioned media and TNF plus IL7-mediated Gfi1 mRNA upregulation and the concomitant Runx2 repression, indicating that XRK3F2's prevention of p62-ZZ domain signaling within preOB is involved in the response. Chromatin immunoprecipitation (ChIP) analyses revealed that XRK3F2 decreased MM-induced GFI1 occupancy at the Runx2-P1 promoter and prevented recruitment of HDAC1, thus preserving the transcriptionally permissive chromatin mark H3K9ac on Runx2 and allowing osteogenic differentiation. Furthermore, treatment of MM-exposed preOB with XRK3F2 after MM removal decreased GFI1 enrichment at Runx2-P1 and rescued MM-induced suppression of Runx2 mRNA and its downstream osteogenic gene targets together with increased osteogenic differentiation. Further, primary BMSC (hBMSC) from MM patients (MM-hBMSC) had little ability to increase H3K9ac on the Runx2 promoter in osteogenic conditions when compared to hBMSC from healthy donors (HD). XRK3F2 treatment enriched Runx2 gene H3K9ac levels in MM-hBMSC to the level observed in HD-hBMSC, but did not alter HD-hBMSC H3K9ac. Importantly, XRK3F2 treatment of long-term MM-hBMSC cultures rescued osteogenic differentiation and mineralization. Our data show that blocking p62-ZZ domain-dependent signaling with XRK3F2 can reverse epigenetic-based mechanisms of MM-induced Runx2 suppression and promote osteogenic differentiation.
DJ-1 Regulates Microglial Polarization Through P62-Mediated TRAF6/IRF5 Signaling in Cerebral Ischemia-Reperfusion
Front Cell Dev Biol 2020 Dec 17;8:593890.PMID:33392187DOI:10.3389/fcell.2020.593890.
The polarization of microglia/macrophage, the resident immune cells in the brain, plays an important role in the injury and repair associated with ischemia-reperfusion (I/R). Previous studies have shown that DJ-1 has a protective effect in cerebral I/R. We found that DJ-1 regulates the polarization of microglial cells/macrophages after cerebral I/R and explored the mechanism by which DJ-1 mediates microglial/macrophage polarization in cerebral I/R. Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen and glucose deprivation/reoxygenation (OGD/R) models were used to simulate cerebral I/R in vivo and in vitro, respectively. DJ-1 siRNA and the DJ-1-based polypeptide ND13 were used to produce an effect on DJ-1, and the P62-specific inhibitor XRK3F2 was used to block the effect of P62. Enhancing the expression of DJ-1 induced anti-inflammatory (M2) polarization of microglia/macrophage, and the expression of the anti-inflammatory factors IL-10 and IL-4 increased. Interference with DJ-1 expression induced pro-inflammatory (M1) polarization of microglia/macrophage, and the expression of the proinflammatory factors TNF-α and IL-1β increased. DJ-1 inhibited the expression of P62, impeded the interaction between P62 and TRAF6, and blocked nuclear entry of IRF5. In subsequent experiments, XRK3F2 synergistically promoted the effect of DJ-1 on microglial/macrophage polarization, further attenuating the interaction between P62 and TRAF6.
A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells
Cancer Lett 2021 Jul 10;510:24-36.PMID:33862150DOI:10.1016/j.canlet.2021.04.003.
There has been an increasing focus on the tumorigenic potential of leukemia initiating cells (LICs) in acute myeloid leukemia (AML). Despite the important role of selective autophagy in the life-long maintenance of hematopoietic stem cells (HSCs), cancer progression, and chemoresistance, the relationship between LICs and selective autophagy remains to be fully elucidated. Sequestosome 1 (SQSTM1), also known as p62, is a selective autophagy receptor for the degradation of ubiquitinated substrates, and its loss impairs leukemia progression in AML mouse models. In this study, we evaluated the underlying mechanisms of mitophagy in the survival of LICs with XRK3F2, a p62-ZZ inhibitor. We demonstrated that XRK3F2 selectively impaired LICs but spared normal HSCs in both mouse and patient-derived tumor xenograft (PDX) AML models. Mechanistically, we observed that XRK3F2 blocked mitophagy by inhibiting the binding of p62 with defective mitochondria. Our study not only evaluated the effectiveness and safety of XRK3F2 in LICs, but also demonstrated that mitophagy plays an indispensable role in the survival of LICs during AML development and progression, which can be impaired by blocking p62.
Interaction between TRPML1 and p62 in Regulating Autophagosome-Lysosome Fusion and Impeding Neuroaxonal Dystrophy in Alzheimer's Disease
Oxid Med Cell Longev 2022 Jan 25;2022:8096009.PMID:35116093DOI:10.1155/2022/8096009.
The loss of transient receptor potential mucolipin 1 (TRPML1), an endosomal and lysosomal Ca2+-releasing channel, has been implicated in neurodegenerative disorders. Mounting evidence have shown that TRPML1 could clear intraneuronal amyloid-β (Aβ), which triggers a hypothesis that TRPML1 activation may be beneficial for axonal transport in Alzheimer's disease (AD). In this work, the functional roles of TRPML1 were studied in the APP/PS1 transgenic mice and Aβ1-42-stimulated hippocampal neurons HT22. We found that lentivirus-mediated overexpression of TRPML1 was shown to promote an accumulation of autolysosomes and increase brain-derived neurotrophic factor (BDNF) transportation to the nucleus, suggesting an axon-protective function. More importantly, we found that TRPML1 also increased p62 that interacted with dynein. Lentivirus-mediated knockdown of p62 or inhibition of dynein by ciliobrevin D stimulation was found to reduce autolysosome formation and nuclear accumulation of BDNF in HT22 cells with Aβ1-42 stimulation. Inhibition of p62 by XRK3F2 stimulation was observed to promote the death of hippocampal neurons of the APP/PS1 transgenic mice. TRPML1 recruited dynein by interacting with p62 to promote the autophagosome-lysosome fusion to mediate BDNF nuclear translocation to impede axon dystrophy in mice with Alzheimer-like phenotypes. In summary, these results demonstrate the presence of a TRPML1/p62/dynein regulatory network in AD, and activation of TRPML1 is required for axon protection to prevent neuroaxonal dystrophy.
Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo
Leukemia 2016 Feb;30(2):390-8.PMID:26286116DOI:10.1038/leu.2015.229.
We reported that p62 (sequestosome 1) serves as a signaling hub in bone marrow stromal cells (BMSCs) for the formation of signaling complexes, including NFκB, p38MAPK and JNK, that are involved in the increased osteoclastogenesis and multiple myeloma (MM) cell growth induced by BMSCs that are key contributors to multiple myeloma bone disease (MMBD), and demonstrated that the ZZ domain of p62 (p62-ZZ) is required for BMSC enhancement of MMBD. We recently identified a novel p62-ZZ inhibitor, XRK3F2, which inhibits MM cell growth and BMSC growth enhancement of human MM cells. In the current study, we evaluate the relative specificity of XRK3F2 for p62-ZZ, characterize XRK3F2's capacity to inhibit growth of primary MM cells and human MM cell lines, and test the in vivo effects of XRK3F2 in the immunocompetent 5TGM1 MM model. We found that XRK3F2 induces dramatic cortical bone formation that is restricted to MM containing bones and blocked the effects and upregulation of tumor necrosis factor alpha (TNFα), an osteoblast (OB) differentiation inhibitor that is increased in the MM bone marrow microenvironment and utilizes signaling complexes formed on p62-ZZ, in BMSC. Interestingly, XRK3F2 had no effect on non-MM bearing bone. These results demonstrate that targeting p62 in MM models has profound effects on MMBD.