更新于：2024-11-01

SLIT2 x ROBO2

更新于：2024-11-01

基本信息

关联

项与 SLIT2 x ROBO2 相关的药物

PF-06730512

靶点

ROBO2 x SLIT2

作用机制

ROBO2 antagonists [+2]

在研机构

Boston University School of Medicine [+2]

原研机构

Pfizer Inc.

在研适应症

局灶性节段性肾小球硬化症

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 SLIT2 x ROBO2 相关的临床试验

NCT03448692 / Terminated临床2期

A PHASE 2, 24-WEEK, ADAPTIVE, OPEN LABEL, SEQUENTIAL COHORT TRIAL TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-06730512 FOLLOWING MULTIPLE DOSES IN ADULT SUBJECTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

The purpose of this Phase 2 adaptive study is to evaluate the efficacy, safety, tolerability and pharmacokinetics of PF-06730512 following multiple intravenous infusions in adult subjects with FSGS.

开始日期2018-10-15

申办/合作机构

Pfizer Inc.

NCT03146065 / Completed临床1期

A Phase 1, Randomized, Double Blind, Sponsor-open, Placebo-controlled, First-in-human Trial To Evaluate The Safety, Tolerability, And Pharmacokinetics Of Pf-06730512 After Single And Multiple Ascending Intravenous Infusion Or Subcutaneous Administration To Healthy Adult Subjects And An Open-label Evaluation In Healthy Japanese Subjects

The purpose of this study is to determine the safety, tolerability and pharmacokinetics of escalating single and multiple intravenous (IV) infusions and subcutaneous (SC) injections of PF-06730512 in healthy subjects.

开始日期2017-05-10

申办/合作机构

Pfizer Inc.

100 项与 SLIT2 x ROBO2 相关的临床结果

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100 项与 SLIT2 x ROBO2 相关的转化医学

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0 项与 SLIT2 x ROBO2 相关的专利（医药）

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105

项与 SLIT2 x ROBO2 相关的文献（医药）

2023-08-01·Life Science Alliance

SLIT2/ROBO1 signaling suppresses mTORC1 for organelle control and bacterial killing

Article

作者: Hua, Rong ; Kim, Peter K ; Tessier-Lavigne, Marc ; Kwon, Hyunwoo ; Patel, Sajedabanu ; Bhosle, Vikrant K ; Li, Zhubing ; Li, Taoyingnan ; Brumell, John H ; Robinson, Lisa A ; Tan, Joel Mj

SLIT/ROBO signaling impacts many aspects of tissue development and homeostasis, in part, through the regulation of cell growth and proliferation. Recent studies have also linked SLIT/ROBO signaling to the regulation of diverse phagocyte functions. However, the mechanisms by which SLIT/ROBO signaling acts at the nexus of cellular growth control and innate immunity remain enigmatic. Here, we show that SLIT2-mediated activation of ROBO1 leads to inhibition of mTORC1 kinase activity in macrophages, leading to dephosphorylation of its downstream targets, including transcription factor EB and ULK1. Consequently, SLIT2 augments lysosome biogenesis, potently induces autophagy, and robustly promotes the killing of bacteria within phagosomes. Concordant with these results, we demonstrate decreased lysosomal content and accumulated peroxisomes in the spinal cords of embryos fromRobo1−/−,Robo2−/−double knockout mice. We also show that impediment of auto/paracrine SLIT-ROBO signaling axis in cancer cells leads to hyperactivation of mTORC1 and inhibition of autophagy. Together, these findings elucidate a central role of chemorepellent SLIT2 in the regulation of mTORC1 activity with important implications for innate immunity and cancer cell survival.

2023-05-01·Biomolecules

The SLIT/ROBO Pathway in Liver Fibrosis and Cancer.

Review

作者: Pi, Liya ; Basha, Sreenivasulu ; Sun, Chunbao ; Jin-Smith, Brady

Liver fibrosis is a common outcome of most chronic liver insults/injuries that can develop into an irreversible process of cirrhosis and, eventually, liver cancer. In recent years, there has been significant progress in basic and clinical research on liver cancer, leading to the identification of various signaling pathways involved in tumorigenesis and disease progression. Slit glycoprotein (SLIT)1, SLIT2, and SLIT3 are secreted members of a protein family that accelerate positional interactions between cells and their environment during development. These proteins signal through Roundabout receptor (ROBO) receptors (ROBO1, ROBO2, ROBO3, and ROBO4) to achieve their cellular effects. The SLIT and ROBO signaling pathway acts as a neural targeting factor regulating axon guidance, neuronal migration, and axonal remnants in the nervous system. Recent findings suggest that various tumor cells differ in SLIT/ROBO signaling levels and show varying degrees of expression patterns during tumor angiogenesis, cell invasion, metastasis, and infiltration. Emerging roles of the SLIT and ROBO axon-guidance molecules have been discovered in liver fibrosis and cancer development. Herein, we examined the expression patterns of SLIT and ROBO proteins in normal adult livers and two types of liver cancers: hepatocellular carcinoma and cholangiocarcinoma. This review also summarizes the potential therapeutics of this pathway for anti-fibrosis and anti-cancer drug development.

2023-03-20·Journal of Clinical Oncology

Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors

Article

作者: Hudson, Melissa M. ; Bhatia, Smita ; Armenian, Saro H. ; Hawkins, Douglas S. ; Ritchey, A. Kim ; Sapkota, Yadav ; Yasui, Yutaka ; Armstrong, Gregory T. ; Landier, Wendy ; Burridge, Paul ; Blanco, Javier G. ; Sharafeldin, Noha ; Chow, Eric J. ; Hageman, Lindsey ; Zhou, Liting ; Oeffinger, Kevin C. ; Wang, Xuexia ; Robison, Leslie L. ; Singh, Purnima ; Neglia, Joseph P. ; Ginsberg, Jill P.

PURPOSE Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication). METHODS A genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1. RESULTS Two SNPs (rs17736312 [ ROBO2]) and rs113230990 (near a CCCTC-binding factor insulator [< 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m2, the AA genotype and anthracyclines > 250 mg/m2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-β1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect ( TGF-β1, P = .007); gene*anthracycline interaction ( ROBO2*anthracycline, P = .0003); and gene*gene*anthracycline interaction ( SLIT2* TGF-β1*anthracycline, P = .009). CONCLUSION These findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-β1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 ( ROBO2) and anthracycline-related cardiomyopathy.

项与 SLIT2 x ROBO2 相关的新闻（医药）

2022-04-02

·新浪医药新闻

辉瑞1类新药注射用PF-06730512在华申报临床拟用于多种肾病

4月2日，CDE官网公示，辉瑞在中国申报了1类新药注射用PF-06730512的临床试验申请。公开资料显示，该产品为辉瑞在研潜在“first-in-class”项目，含ROBO2配体（SLIT）陷阱。公开资料显示，该产品为辉瑞在研潜在“first-in-class”项目，含ROBO2配体（SLIT）陷阱。目前，该产品在全球正处于2期临床研究阶段，拟开发用于治疗一种罕见进行性肾病。 ROB0是与发育有关的跨膜受体家族，包括ROB01、ROB02、ROB03、ROB04这4个成员。其中，ROB02主要表达于神经系统，对神经轴突导向和神经细胞迁移有重要的调控作用。R0B02为细胞黏附分子免疫球蛋白，是SLIT1和SLIT2的受体。SLIT-ROB0信号转导通路通过多种不同的下游信号转导途径实现其多种多样的生物学功能，不仅可引起轴突导向生长、神经元细胞迁移，而且可对非神经细胞的细胞迁移也具有重要的调控作用，如白细胞、肌细胞、血管内皮细胞、血管平滑肌细胞等。根据辉瑞公开资料介绍，PF-06730512是该公司开发的含ROBO2配体陷阱（ligand trap）的创新生物制品，有望改变疾病进程。配体陷阱是一种重组分子，包含相关配体结合结构域，能以高特异性和高亲和力结合其相应的细胞因子。PF-06730512能够改善肾脏足细胞的功能，因此有望开发用于治疗多种和足细胞相关的蛋白尿性肾小球疾病。此前，PF-06730512已在治疗局灶节段性肾小球硬化（FSGS）的2a期临床试验中获得积极研究结果。FSGS是一种罕见进行性肾病，大约60%的患者在5~10年内会发展成终末期肾病。中期分析显示，PF-06730512可以在耐药性患者中，显著降低患者尿蛋白肌酐比值（UPCR）。同时，该产品每两周一次的治疗耐受性良好，没有观察到明显的安全性信号。内容来源于网络，如有侵权，请联系删除，谢谢。

First in Class