更新于：2024-11-01

FANCL

更新于：2024-11-01

基本信息

别名

E3 ubiquitin-protein ligase FANCL、FA complementation group L、FAAP43

+ [7]

简介

Ubiquitin ligase protein that mediates monoubiquitination of FANCD2 in the presence of UBE2T, a key step in the DNA damage pathway (PubMed:12973351, PubMed:16916645, PubMed:17938197, PubMed:19111657, PubMed:24389026). Also mediates monoubiquitination of FANCI (PubMed:19589784). May stimulate the ubiquitin release from UBE2W. May be required for proper primordial germ cell proliferation in the embryonic stage, whereas it is probably not needed for spermatogonial proliferation after birth.

关联

项与 FANCL 相关的药物

SKY-1214

靶点

FANCI x FANCL

作用机制

FANCI modulators [+2]

在研机构

Sanofi [+1]

原研机构

Skyhawk Therapeutics, Inc.初创企业

在研适应症

多发性骨髓瘤 [+2]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FANCL 相关的临床结果

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100 项与 FANCL 相关的转化医学

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0 项与 FANCL 相关的专利（医药）

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195

项与 FANCL 相关的文献（医药）

2024-10-01·Current Medicinal Chemistry

A Risk Model Developed based on Homologous Recombination Deficiency Genes for Evaluating the Drug Sensitivity and Prognostic Prediction of Lung Adenocarcinoma

Article

作者: Hong, Lingling ; Li, Jiashun ; Shao, Weiwei

Aim:This study was designed to construct a risk model based on homologous recombination deficiency (HRD) to evaluate the prognosis and drug sensitivity for patients with lung adenocarcinoma (LUAD).Background:LUAD is a subtype of lung cancer with unfavorable overall survival (OS) and prognosis. HRD has been widely studied in various tumors, but its role in LUAD has not been fully understood.Objective:We aimed to construct an HRD-related risk model for predicting the prognosis and drug sensitivity of patients with LUAD.Methods:Gene expression data of the LUAD samples were collected from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We extracted HRD genes from previous literature and performed univariate COX analysis to select those closely associated with LUAD prognosis. ConsensusClusterPlus was employed to stratify the samples in the TCGA-LUAD cohort into different subtypes. A RiskScore model was established applying random forest method. Furthermore, immunotherapy response and drug sensitivity were predicted using Tumor Immune Dysfunction and Exclusion (TIDE) software and pRRophytic R package, respectively. Finally, the clinical features between High- and Low- RiskScore groups were compared.Results:A total of 16 HRD genes relevant to LUAD prognosis were selected and used to classify 3 LUAD clusters (C1, C2, and C3). Specifically, C1, with a lower TIDE score displayed higher immune infiltration and immunotherapy benefit and the optimal OS, while C2 was closely correlated with tumor-relevant pathways and had the worst OS. Finally, 4 HRD genes (RAD51AP1, BRCA1, H2AFX, and FANCL) were determined to develop a RiskScore signature. It was found that a higher RiskScore was related to more advanced stages, worse OS, and tumor development pathways. Additionally, the High-RiskScore group with a higher TIDE score was sensitive to 44 traditional chemotherapy drugs. A nomogram combined with RiskScore exhibited an accurate survival prediction ability.Conclusion:The HRD-based RiskScore played a crucial role in LUAD development, showing a strong potential to serve as a prognostic indicator for LUAD. Our findings contributed to the diagnosis of LUAD and its treatment.

2024-07-17·Biochemical Journal

E3 ligases: a ubiquitous link between DNA repair, DNA replication and human disease

Review

作者: Stewart, Grant S. ; Jhujh, Satpal S. ; Chauhan, Anoop S.

Maintenance of genome stability is of paramount importance for the survival of an organism. However, genomic integrity is constantly being challenged by various endogenous and exogenous processes that damage DNA. Therefore, cells are heavily reliant on DNA repair pathways that have evolved to deal with every type of genotoxic insult that threatens to compromise genome stability. Notably, inherited mutations in genes encoding proteins involved in these protective pathways trigger the onset of disease that is driven by chromosome instability e.g. neurodevelopmental abnormalities, neurodegeneration, premature ageing, immunodeficiency and cancer development. The ability of cells to regulate the recruitment of specific DNA repair proteins to sites of DNA damage is extremely complex but is primarily mediated by protein post-translational modifications (PTMs). Ubiquitylation is one such PTM, which controls genome stability by regulating protein localisation, protein turnover, protein-protein interactions and intra-cellular signalling. Over the past two decades, numerous ubiquitin (Ub) E3 ligases have been identified to play a crucial role not only in the initiation of DNA replication and DNA damage repair but also in the efficient termination of these processes. In this review, we discuss our current understanding of how different Ub E3 ligases (RNF168, TRAIP, HUWE1, TRIP12, FANCL, BRCA1, RFWD3) function to regulate DNA repair and replication and the pathological consequences arising from inheriting deleterious mutations that compromise the Ub-dependent DNA damage response.

2024-07-05·The Oncologist

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis

Article

作者: Parma, Gabriella ; Curigliano, Giuseppe ; Fusco, Nicola ; Marra, Antonio ; Belli, Carmen ; Crimini, Edoardo ; Colombo, Nicoletta ; Repetto, Matteo ; Setola, Elisabetta ; Boscolo Bielo, Luca ; Guerini Rocco, Elena ; Barberis, Massimo

AbstractBackgroundUterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors.MethodsTo investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB.Clinical Report and ResultsWe reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered.ConclusionuLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.

项与 FANCL 相关的新闻（医药）

2024-10-25

·PipelineReview

Skyhawk Therapeutics Presents Compelling Preclinical Data on SKY-1214 at the EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium

SKY-1214, an IND-ready first-in-class FANCL/FANCI RNA splicing modulator, demonstrates tumor growth inhibition and regression to undetectable levels in NHL and difficult-to-treat MM xenograft mouse models BOSTON, MA, USA I October 24, 2024 I Skyhawk Therapeutics, Inc., a clinical-stage biotechnology company developing novel small molecule therapies designed to modulate critical RNA targets, today announced that the Company presented compelling preclinical data highlighting the therapeutic potential of its first-in-class compound, SKY-1214, at the European Organization for Research and Treatment of Cancer (EORTC)-National Cancer Institute (NCI)-American Association for Cancer Research (AACR) Molecular Targets and Cancer Therapeutics Symposium (“EORTC-NCI-AACR” or the “Triple Meeting”). SKY-1214 is a first-in-class, oral RNA splicing modulator discovered through the company’s novel RNA-splicing platform and being developed for difficult-to-treat multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL). SKY-1214 targets FANCL/FANCI, critical components of the Fanconi anemia DNA damage repair pathway, which MM and NHL cells use to maintain their genome integrity. Study authors concluded that SKY-1214 shows potent and efficacious anti-cancer activity in MM and NHL models in vitro , including in models with high-risk cytogenetic and/or genetic alterations (e.g., t(14;16), t(4;14), 1q+, and double-hit lymphoma). Additionally, in vivo treatment with SKY-1214 as a monotherapy resulted in tumor growth inhibition and regression to undetectable levels at tolerated doses in NHL and difficult-to-treat MM xenograft mouse models, including KMS-28BM. “We’re excited to present these data and to introduce SKY-1214, our most-advanced oncology program, ready for IND submission,” said Sergey Paushkin, M.D., Ph.D., Co-founder, Head of R&D at Skyhawk. “There are a number of approved treatments for both MM and NHL, but all patients with MM eventually progress and only 50% of patients with certain NHL subtypes can be cured, underscoring the urgent need for new therapies with novel mechanisms of action. SKY-1214’s profound anti-cancer activity, including in these high-risk tumor cell lines, supports further development and exploration as a single agent and in combination treatment in these difficult-to-treat cancers.” The poster is available on the Skyhawk website at www.skyhawktx.com/resources . About SKY-1214 SKY-1214 is a first-in-class, oral FANCL/FANCI targeting RNA splicing modulator being developed for difficult to treat multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL). FANCL/FANCI are critical components of the Fanconi anemia DNA damage repair pathway, which MM and NHL tumor cells use to maintain their genome integrity. Skyhawk has observed anti-tumor activity for SKY-1214 in a number of preclinical cell models, including those representing prevalent high-risk cytogenetic alterations. SKY-1214 also demonstrated anti-tumor activity in human tumor cell-derived xenograft mouse models correlating with FANCL/FANCI mRNA reduction. SKY-1214 has completed IND-enabling studies. About Skyhawk Therapeutics Skyhawk Therapeutics is a clinical-stage biotechnology company focused on the discovery and development of novel small molecule therapies designed to modulate critical RNA targets and revolutionize patient treatment for some of the world’s most intractable diseases. Skyhawk’s discovery expertise is rooted in its proprietary drug discovery platform, which assesses, identifies, and tests RNA splicing targets and small molecules across a broad range of therapeutic areas and disease states. Skyhawk has built collaborations with multiple pharma partners that leverage Skyhawk’s novel platform across disease areas including neurodegenerative disease, autoimmune disease, and oncology. For more information visit www.skyhawktx.com . SOURCE: Skyhawk Therapeutics

AACR会议siRNA

2024-04-26

·生物谷

18亿美元！Ipsen与Skyhawk合作开发RNA靶向的小分子，治疗罕见神经系统疾病

目前，Skyhawk全资拥有的研发管线包括神经退行性疾病、肿瘤学、神经肌肉、纤维化和其他疾病类型，大多是针对以前被认为对于传统蛋白质靶点来说的“不可成药靶点”。 Ipsen公司和Skyhawk Therapeutic宣布签署一项全球独家合作协议，以发现和开发用于治疗罕见神经系统疾病的RNA靶向的小分子药物。Ipsen将向Skyhawk支付一笔未公开金额的预付款，以获得Skyhawk开发的两款候选药物的全球权益，Skyhawk负责临床前开发，Ipsen负责后续临床开发和商业化。该合作的预付款、里程碑付款及潜在的分级特许权使用费总额高达18亿美元。 Skyhawk公司致力于通过开发改变RNA表达的小分子疗法来彻底改变疾病治疗。RNA的错误表达会导致许多疾病，从罕见病、神经系统疾病到癌症。对于这些具有挑战性的病症，可用的治疗方法很少，其中许多疾病被认为是“不可成药的”。目前认为26%的人类蛋白质与疾病相关，但只有3%的人类蛋白质可以使用传统的蛋白质靶向方法来成药的。Skyhawk公司认为，通过小分子药物靶向并调控RNA的表达，从上游改变驱动疾病的蛋白质水平，从而解决不可成药难题。 Skyhawk公司在快速发展的机器学习模型中集成了四个不同且互补的数据集，加速了针对一系列RNA靶点的小分子候选药物的开发。 SKYSTAR®是一种靶点评估系统，集成了来自公共和专有生物信息、结构和计算生物学数据集的数据，以优先考虑高价值的RNA靶点。Skyhawk公司已通过SKYSTAR系统筛选了超过700个靶点。 SKYLIBRARYTM是Skyhawk公司特有的、定制且快速扩展中的RNA靶向化合物库。 SKYSEQTM是Skyhawk公司特有的多重筛选系统，可同时测试一系列RNA序列中的数十个高价值靶点，以识别对特定疾病靶点具有选择性的化合物。 SKYAITM是Skyhawk公司的机器学习工具，集成了来自SKYSTAR、医学化学、动物研究、毒性数据和临床项目的数据，以推动下一代新型RNA剪接调节剂的开发。凭借其先进的药物发现平台，Skyhawk公司已经与BMS、渤健、基因泰克、默克、赛诺菲、Vertex等大型制药公司达成了合作协议。 Skyhawk开发的治疗亨廷顿症的RNA靶向的小分子药物SKY-0515正在进行1期临床试验，治疗多发性骨髓瘤和非霍奇金淋巴瘤的RNA靶向的小分子药物SKY-1214预计将在今年年底开启临床试验。目前，Skyhawk全资拥有的研发管线包括神经退行性疾病、肿瘤学、神经肌肉、纤维化和其他疾病类型，大多是针对以前被认为对于传统蛋白质靶点来说的“不可成药靶点”。此外，Skyhawk还与多家大型制药公司合作了十多个保密的临床前项目，涉及神经退行性疾病、肿瘤学、神经肌肉、罕见疾病和其他疾病类型。 Skyhawk研发管线