更新于：2024-05-01
c-Cbl
Cbl proto-oncogene
更新于：2024-05-01
基本信息
别名 c-Cbl、Casitas B-lineage lymphoma proto-oncogene、CBL + [8] |
简介 Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome (PubMed:17094949). Ubiquitinates SPRY2 (PubMed:17094949, PubMed:17974561). Ubiquitinates EGFR (PubMed:17974561). Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity). |
关联
100 项与 c-Cbl 相关的临床结果
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100 项与 c-Cbl 相关的转化医学
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0 项与 c-Cbl 相关的专利（医药）
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2,916
项与 c-Cbl 相关的文献（医药）2024-04-01·Journal of Taibah University Medical Sciences
Associations among gene polymorphisms, crestal bone loss, and bone mineral density in patients receiving dental implants.
Article
作者: Kaushal Kishor Agrawal ; Neetu Singh ; Pooran Chand ; Saumyendra Vikram Singh ; Neeti Solanki ; Ravindra Kumar Garg ; Akhilanand Chaurasia
Objectives:
Interleukin 1 (IL-1) and interleukin 6 (IL-6) gene polymorphisms have been suggested to be responsible for diminished bone mineral density (BMD) and high crestal bone loss (CBL) in some individuals. However, the effects of systemic BMD on variations in peri-implant CBL are unclear. Hence, this study was aimed at investigating the association of IL-1 and IL-6 gene polymorphisms with systemic BMD and CBL around dental implants.
Methods:
A total of 190 participants undergoing dental implantation in the mandibular posterior region were selected according to predetermined selection criteria and divided into a normal BMD group (NBD, 93 participants, T-score ≥ -1) and low BMD group (LBD, including both osteoporosis and osteopenia, 97 participants, T-score < -1 standard deviation) according to the BMD of the right femoral neck, measured with dual-energy X-ray absorptiometry. Dental implants were placed through the standard surgical protocol, and CBL was calculated after 6 months with cone beam computed tomography scans before second-stage surgery. Genotyping was performed on all participants for IL-1A-889 A/G, IL-1B-511G/A, IL-1B+3954, and IL-6-572 C/G gene polymorphisms.
Results:
The demographic and clinical characteristics of the participants in both groups were compared with t-test and chi-square test (χ2). The associations of NBD and LBD with the different genotypes and CBL was determined with odds ratios, and p < 0.05 was considered statistically significant. The frequency of IL-1B-511AA and IL-6-572 GG genotypes was significantly higher in LBD than in NBD (p < 0.05). In LBD, the IL-1B-511 AA (AA vs GA + GG; p ≤ 0.001) and IL-6-572 GG (GG vs CC + GC; p = 0.001) genotypes were significantly associated with higher peri-implant CBL.
Conclusions:
Individuals with the IL-1B-511 AA or IL-6-572 GG genotype had elevated risk of osteoporosis/osteopenia and were more susceptible to CBL around dental implants.
2024-02-01·Zhongguo shi yan xue ye xue za zhi
[The Study of Recombinant Interfering Lentiviruses and Overexpressed Adenovirus Vectors Targeting Human c-Cbl Gene： Construction, Identification and Efficacy].
Article
作者: Qi-Xin Sun ; Bing-Yi Wu ; Qian-Qian Yao ; Zhi-Wei Huang ; Zhi-Gang Zhu
OBJECTIVE:
To construct recombinant lentivirus and adenovirus which regulate the expression of c-Cbl gene and evaluate their efficacy.
METHODS:
The interference lentivirus and overexpressed adenovirus targeting human c-Cbl gene were constructed by gene recombination technology. Quantitative PCR and western blotting were used to detect the expression changes in c-Cbl gene and its transcription after leukemia cells (HL60,THP1) were infected by virus.
RESULTS:
Three recombinant interfering lentiviral vectors targeting human c-Cbl genes to successfully constructed and were identified by DNA sequencing, and the titers of the packaged viruses were all greater than 1×108 TU/ml. Among them, shRNA-2 lentivirus had the highest interference efficiency, and the expression of c-Cbl gene and CBL protein were decreased about 95% and 60% respectively after leukemia cells were infected with shRNA-2; In addition, the recombinant overexpression adenovirus targeting human c-Cbl gene was packaged successfully with the virus titer greater than 1×109 TU/ml. When leukemia cells were infected with adenovirus, the expression of c-Cbl gene and CBL protein were up-regulated about 10 times and 1.5 times respectively.
CONCLUSION:
Both recombinant interfering lentivirus and overexpression adenovirus can efficiently infect leukemia cells and affect the expressions of c-Cbl gene and CBL protein. It will lay a preliminary foundation for the subsequent study on the function of c-Cbl gene in tumor cells.
2024-01-27·Nutrients
Kinetics of Cellular Cobalamin Uptake and Conversion: Comparison of Aquo/Hydroxocobalamin to Cyanocobalamin.
Article
作者: Sergey N Fedosov ; Ebba Nexo ; Christian W Heegaard
Cyanocobalamin (CNCbl) and aquo/hydroxocobalamin (HOCbl) are the forms of vitamin B12 that are most commonly used for supplementation. They are both converted to methylcobalamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl), which metabolize homocysteine and methylmalonic acid, respectively. Here, we compare the kinetics of uptake and the intracellular transformations of radiolabeled CNCbl vs. HOCbl in HeLa cells. More HOCbl was accumulated over 4-48 h, but further extrapolation indicated similar uptake (>90%) for both vitamin forms. The initially synthesized coenzyme was MeCbl, which noticeably exceeded AdoCbl during 48 h. Yet, the synthesis of AdoCbl accelerated, and the predicted final levels of Cbls were MeCbl ≈ AdoCbl ≈ 40% and HOCbl ≈ 20%. The designed kinetic model revealed the same patterns of the uptake and turnover for CNCbl and HOCbl, apart from two steps. First, the "activating" intracellular processing of the internalized HOCbl was six-fold faster. Second, the detachment rates from the cell surface (when the "excessive" Cbl-molecules were refluxed into the external medium) related as 4:1 for CNCbl vs. HOCbl. This gave a two-fold faster cellular accumulation and processing of HOCbl vs. CNCbl. In medical terms, our data suggest (i) an earlier response to the treatment of Cbl-deficiency with HOCbl, and (ii) the manifestation of a successful treatment initially as a decrease in homocysteine.
16
项与 c-Cbl 相关的新闻（医药）2023-12-28
免疫检查点是免疫系统的负反馈机制，激活后保护正常细胞免受T细胞介导的细胞毒性，维持免疫稳态。熟知的检查点（PD-(L)1、CTLA-4、TIM3、LAG3等）表达于细胞膜表面。除此之外，一些细胞内蛋白参与 TCR 下游的负反馈回路，可被视为胞内免疫检查点（(intracellular
immune checkpoints ，iICPs)，目前有多个在临床研究阶段。SHP-2（Src homology region 2）PD-1可通过招募磷酸酶SHP-2来抑制T细胞的活化。然而，T细胞特异性缺失SHP2的小鼠并没有改善抗肿瘤免疫。后来发现，在没有SHP-2的情况下，PD-1招募了SHP-1来维持此功能。因此，同时阻断SHP-1和SHP-2对于改善TCR信号通路是必要的。Front. Immunol. 2019在骨髓中，GM-CSF诱导PD-1的磷酸化，PD-1-SHP-2的募集到GM-CSF受体。SHP-2或PD-1的缺失增强了GM-CSF介导的转录因子HOXA10和IRF8的磷酸化，这分别调节髓系分化和单核-moDC谱系分化。因此，SHP-2和PD1-SHP-2信号抑制髓细胞分化，产生抑制性髓系细胞，抑制抗肿瘤免疫。此外，SHP-2是生长因子-ERK信号通路的重要调节分子。抗PD-1抗体与SHP-2抑制剂联合的临床研究ICP-189 诺诚健华NCT05370755：A Study of ICP-189 and ICP-189 in Combination With Anti-PD-1 Monoclonal Antibody in Patients With Advanced Solid Tumors。BBP-398 Navire Pharma Inc., a BridgeBio companyNCT05375084：SHP2 Inhibitor BBP-398 in Combination With Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer With a KRAS Mutation。单药及与小芬抑制剂联合TNO155 Novartis NCT03114319 Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors（单药或联合EGF816 (nazartinib)HBI-2376 沪亚生物NCT05163028 A Dose Escalation Study of SHP2 Inhibitor in Patients With Solid Tumors Harboring KRAS of EGFR Mutations HS-10381 江苏豪森药业NCT05378178 A PhaseⅠStudy of HS-10381 in Patients With Advanced Solid Tumors ET0038 上海奕拓医药NCT05354843 SHP2 Inhibitor ET0038 Monotherapy in Patients With Advanced Solid TumorsJAB-3068 加科思NCT03565003 A First-in-Human Study of JAB-3068 (SHP2 Inhibitor) in Adult Patients With Advanced Solid Tumors in ChinaJAB-3312 加科思NCT05288205 Phase 1/2a Study of JAB-21822 Plus JAB-3312 in Patients With Advanced Solid Tumors Harboring KRAS p.G12C MutationERAS-601 Erasca, Inc.(Nasdaq: ERAS)NCT04866134 A Study of ERAS-007 as Monotherapy or in Combination With ERAS-601 in Patients With Advanced or Metastatic Solid Tumors (HERKULES-1)NCT04670679 A Dose Escalation/Expansion Study of ERAS-601 in Patients With Advanced or Metastatic Solid Tumors (FLAGSHP-1)PF-07284892 辉瑞NCT04800822 PF-07284892 in Participants With Advanced Solid TumorsRMC-4630 Revolution Medicines, Inc.NCT05054725 Combination Study of RMC-4630 and Sotorasib for NSCLC Subjects With KRASG12C Mutation After Failure of Prior Standard TherapiesCbl-bCbl-b是CBL(Casitas B-lymphoma))家族的一个成员。CBL蛋白具有环指催化结构域，负责蛋白质泛素化和目标蛋白的顺序降解。CBL蛋白导致多个靶点的降解，从而下调TCR信号级联。Cbl-b靶向PI3K的调控亚基p85，降低了PI3K的活性，干扰其激活不同信号通路的能力。Cbl-b参与调控CD28或抑制受体CTLA-4和PD-1的共刺激信号，TCR上Cbl-b的丢失导致Akt/Erk磷酸化、增殖、激活、细胞因子的产生（IFNγ、TNFα、IL-2）和细胞溶解能力（颗粒酶B）。Journal for ImmunoTherapy of Cancer 2023一些抑制T细胞CBL-b的临床试验正在进行中。CISH一个SOCS（细胞因子信号抑制因子）家族蛋白成员，负调控CD8+ T细胞信号通路。缺陷小鼠的CD8+ T淋巴细胞对TCR信号响应改善，效应功能相关基因（Il2、Prf1、GrzmB、Eomes、Tbx21、c-Myc和Bcl2l）的表达增加。通过CRISPR-Cas9敲除TILs中CISH，进行肿瘤治疗的临床试验正在进行中。Cells 2021HPK1造血祖细胞激酶 1 （Hematopoietic progenitor kinase 1，HPK1） 由 MAP4K1 基因编码，是一种蛋白激酶，被确定为 TCR 信号转导的关键调节因子。Expert Opinion on Therapeutic Patents（2021）HPK1被 TCR 复合物激活，HPK1 结合并磷酸化 LAT 信号小体上的SLP-76。磷酸化的SLP-76随后与GAD和14-3-3蛋白结合，破坏了SLP-76与LAT信号体的相互作用，从而触发了SLP-76降解，SLP-76降解对MAPK-ERK通路信号转导产生负调控。小鼠中的 HPK1基因敲除导致 T 细胞增殖、活化和细胞因子分泌增加，从而赋予它们控制肿瘤生长的能力。许多HPK1小分子抑制剂正在进行癌症免疫治疗临床试验。CFI-402411 Treadwell Therapeutics, IncNCT04521413 Safety and Efficacy Study of CFI-402411 in Subjects With Advanced Solid MalignanciesRGT-264 锐格医药 NCT05764915 A Phase I Study of RGT-264 in Subjects With Advanced Solid TumorsBGB-26808 百济神州NCT05981703 A Study Investigating BGB-26808 Alone or in Combination With Tislelizumab in Participants With Advanced Solid TumorsPF-07265028 辉瑞NCT05233436 PF-07265028 As Single Agent And In Combination With Sasanlimab in Advanced or Metastatic Solid TumorsNDI 1150-101 Nimbus Saturn, Inc.NCT05128487 A Study of NDI 1150-101 in Patients With Solid Tumors参考文献Anthos Christofides etal, SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses，Nat Immunol. 2023 Jan;24(1):55-68Niogret C, Birchmeier W and
Guarda G (2019) SHP-2 in
Lymphocytes’ Cytokine and Inhibitory
Receptor Signaling.
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doi: 10.3389/fimmu.2019.02468Augustin RC, Bao R,
Luke JJ. Targeting Cbl-b in
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2023;11:e006007. doi:10.1136/
jitc-2022-00600Kumar, S.; Sarthi, P.; Mani,
I.; Ashraf, M.U.; Kang, M.-H.; Kumar,
V.; Bae, Y.-S. Epitranscriptomic
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Intracellular Checkpoint CISH. Cells
2021, 10, 2250. https://doi-org.libproxy1.nus.edu.sg/
10.3390/cells10092250 Ian D Linney & Neelu Kaila (2021): Inhibitors of immuno-oncology
target HPK1 – a patent review (2016 to 2020), Expert Opinion on Therapeutic Patents, DOI:
10.1080/13543776.2021.1924671
2023-11-03
Preclinical data highlight potential target engagement biomarkers to support clinical evaluation of CBL-B inhibitors
BOSTON, Nov. 3, 2023 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced the presentation of additional preclinical data from the Company's Casitas B-lineage lymphoma proto-oncogene (CBL-B) program in a poster presentation at the 2023 Society for Immunotherapy of Cancer (SITC) Annual Meeting.
"Our enthusiasm for the therapeutic potential of HST-1011, a potential best-in-class CBL-B inhibitor, is partly driven by our belief that it can drive single-agent biological activity," said Timothy Reilly, Ph.D., Chief Development Officer of HotSpot. "Understanding which peripheral biomarkers are associated with this biology and the reliability of their measurement is critical to our characterization of of HST-1011's activity in patients as we advance our ongoing Phase 1/2 study."
The presentation describes preclinical data in which HotSpot CBL-B inhibitors were evaluated in both in vitro and in vivo settings to identify and then characterize a repertoire of potential proximal biomarkers of CBL-B inhibitory activity. Several proteins, including phosphorylated ZAP70, Notch1 and IGF1R, showed robust dose-dependent effects and were further assessed for their reliability and potential feasibility for use in a clinical setting. The results provide support for their potential use in evaluating HST-1011 in our ongoing Phase 1/2, open-label, clinical study designed to evaluate HST-1011 alone and subsequently in combination with Regeneron's anti-PD-1 therapy, Libtayo® (cemiplimab), in patients with advanced solid tumors that are relapsed on or are refractory to anti-PD(L)-1 or standard of care therapies. Information on this clinical trial can be found on (NCT05662397).
About HST-1011
HST-1011 is an investigational orally bioavailable, selective, small molecule allosteric inhibitor of CBL-B, an E3 ubiquitin protein ligase critically involved in immune cell response. Because CBL-B functions as a master regulator of effector cell (T cell and natural killer cell) immunity, its inactivation removes its endogenous negative regulatory functions to substantially enhance anti-tumor immunity. Preclinical data has demonstrated HST-1011's ability to bind to and inhibit a natural hotspot on CBL-B, yielding the activation and propagation of a targeted anti-tumor immune response. Enabled by HotSpot's proprietary Smart Allostery™ platform, HST-1011 is designed with tight binding, low nanomolar potency, a slow dissociation rate from the target to enable sustained pharmacology, and greater selectivity for CBL-B relative to C-CBL.
About HotSpot Therapeutics, Inc.
HotSpot Therapeutics, Inc. is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit .
Investor & Media Contact:
Natalie Wildenradt
[email protected]
SOURCE HotSpot Therapeutics
免疫疗法AACR会议
2023-09-27
BOSTON, Sept. 27, 2023 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced it will present additional preclinical data from the Company's CBL-B program in a poster presentation at the 2023 Society for Immunotherapy of Cancer (SITC) Annual Meeting, taking place November 1-5, 2023, in San Diego, CA.
Presentation details are as follows:
Title: Exploring Proximal Biomarkers of CBL-B Inhibition in Human Peripheral Blood Mononuclear Cells
Session Date and Time: Fri., Nov. 3, 9:00 AM-7:00 PM PT
Location: Exhibit Halls A and B1, San Diego Convention Center
Abstract Number: 55
About HST-1011
HST-1011 is an investigational orally bioavailable, selective, small molecule allosteric inhibitor of CBL-B, an E3 ubiquitin protein ligase critically involved in immune cell response. Because CBL-B functions as a master regulator of effector cell (T cell and natural killer cell) immunity, its inactivation removes its endogenous negative regulatory functions to substantially enhance anti-tumor immunity. Preclinical data has demonstrated HST-1011's ability to bind to and inhibit a natural hotspot on CBL-B, yielding the activation and propagation of a targeted anti-tumor immune response. Enabled by HotSpot's proprietary Smart Allostery™ platform, HST-1011 is designed with tight binding, low nanomolar potency, a slow dissociation rate from the target to enable sustained pharmacology, and greater selectivity for CBL-B relative to C-CBL.
About HotSpot Therapeutics, Inc.
HotSpot Therapeutics, Inc. is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit .
Investor & Media Contact:
Natalie Wildenradt
[email protected]
SOURCE HotSpot Therapeutics
免疫疗法AACR会议
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