XL-844(XL-844) - 药物靶点：Chk1 x Chk2_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

Chk1 x Chk2

作用机制

Chk1抑制剂(检测点激酶1抑制剂)、Chk2抑制剂(检测点激酶2抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病

在研适应症-

非在研适应症

晚期癌症慢性淋巴细胞白血病淋巴瘤+ [1]

原研机构

Exelixis, Inc.

在研机构-

非在研机构

Exelixis, Inc.

最高研发阶段终止临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

登录后查看时间轴

结构

分子式C14H17N5O2

InChIKeyUVSSZSQSZGKMAL-UHFFFAOYSA-N

CAS号631864-00-1

关联

2

项与 XL-844 相关的临床试验

NCT00234481 / Terminated临床1期

A Phase 1 Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of XL844 Administered Orally to Subjects With Chronic Lymphocytic Leukemia

The purpose of this study is to assess the safety and tolerability of different doses of XL844 when given orally to adults with recurrent or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

开始日期-

申办/合作机构

Exelixis, Inc.

NCT00475917 / Terminated临床1期

A Phase 1 Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of XL844 Administered as a Single Agent and in Combination With Gemcitabine in Subjects With Advanced Malignancies

The purpose of this study is to determine a safe dose of XL844 in combination with gemcitabine, how often it should be taken, and how well people with cancer tolerate the combination of gemcitabine and XL844.

开始日期2007-05-01

申办/合作机构

Exelixis, Inc.

100 项与 XL-844 相关的临床结果

登录后查看更多信息

100 项与 XL-844 相关的转化医学

登录后查看更多信息

100 项与 XL-844 相关的专利（医药）

登录后查看更多信息

5

项与 XL-844 相关的文献（医药）

2020-12-01·BMC Cancer2区 · 医学

A key genomic signature associated with lymphovascular invasion in head and neck squamous cell carcinoma

2区 · 医学

ArticleOA

作者: Xie, Tao ; Jiang, Hualong ; Zhang, Jiexia ; Zhang, Jian ; Lin, Huaming ; Li, Rong ; Yuan, Yawei ; Lin, Jie ; Xu, Anan ; Huang, Xiaoting ; Jiang, Huali ; Wang, Baiyao

AbstractBackgroundLymphovascular invasion (LOI), a key pathological feature of head and neck squamous cell carcinoma (HNSCC), is predictive of poor survival; however, the associated clinical characteristics and underlying molecular mechanisms remain largely unknown.MethodsWe performed weighted gene co-expression network analysis to construct gene co-expression networks and investigate the relationship between key modules and the LOI clinical phenotype. Functional enrichment and KEGG pathway analyses were performed with differentially expressed genes. A protein–protein interaction network was constructed using Cytoscape, and module analysis was performed using MCODE. Prognostic value, expression analysis, and survival analysis were conducted using hub genes; GEPIA and the Human Protein Atlas database were used to determine the mRNA and protein expression levels of hub genes, respectively. Multivariable Cox regression analysis was used to establish a prognostic risk formula and the areas under the receiver operating characteristic curve (AUCs) were used to evaluate prediction efficiency. Finally, potential small molecular agents that could target LOI were identified with DrugBank.ResultsTen co-expression modules in two key modules (turquoise and pink) associated with LOI were identified. Functional enrichment and KEGG pathway analysis revealed that turquoise and pink modules played significant roles in HNSCC progression. Seven hub genes (CNFN, KIF18B, KIF23, PRC1, CCNA2, DEPDC1, and TTK) in the two modules were identified and validated by survival and expression analyses, and the following prognostic risk formula was established: [risk score = EXPDEPDC1 * 0.32636 + EXPCNFN * (− 0.07544)]. The low-risk group showed better overall survival than the high-risk group (P < 0.0001), and the AUCs for 1-, 3-, and 5-year overall survival were 0.582, 0.634, and 0.636, respectively. Eight small molecular agents, namely XL844, AT7519, AT9283, alvocidib, nelarabine, benzamidine, L-glutamine, and zinc, were identified as novel candidates for controlling LOI in HNSCC (P < 0.05).ConclusionsThe two-mRNA signature (CNFN and DEPDC1) could serve as an independent biomarker to predict LOI risk and provide new insights into the mechanisms underlying LOI in HNSCC. In addition, the small molecular agents appear promising for LOI treatment.

2011-06-01·Investigational New Drugs3区 · 医学

A novel Chk inhibitor, XL-844, increases human cancer cell radiosensitivity through promotion of mitotic catastrophe

3区 · 医学

Article

作者: Fumihiko Matsumoto ; Oliver Riesterer ; Jessica Pickett ; Uma Giri ; Uma Raju ; Luka Milas ; David Molkentine ; Li Wang

Check point kinases (Chk) play a major role in facilitating DNA repair upon radiation exposure. We tested the potency of a novel inhibitor of Chk1 and Chk2, XL-844 (provided by Exelixis Inc., CA, USA), to radiosensitize human cancer cells grown in culture and investigated the underlying mechanisms. HT-29 cells (a human colon cancer line) were exposed to XL-844, radiation, or both, and assessed for clonogenic cell survival. Treatment-dependent effects on phosphorylated forms of Chk proteins were assessed by Western blots. Further mechanistic investigations in HT-29 cells included cell cycle analysis by flowcytometry and assessment of DNA repair kinetics by immuno-cytochemistry (ICC) for nuclear appearance of the phosphorylated form of histone 2AX protein (γ-H2AX) staining. Cells undergoing mitotic catastrophe were identified by irregular pattern of mitotic spindle markers α and γ-tubulin staining by ICC. XL-844 enhanced radiosensitivity in a dose and schedule-dependent manner and the enhancement factor was 1.42 at 0.5 survival fraction. Mechanistically XL-844 abrogated radiation-induced Chk2 phosphorylation, induced pan-nuclear γ-H2AX, and prolonged the presence of radiation-induced γ-H2AX foci, and promoted mitotic catastrophe. In conclusion, our data showed that inhibition of Chk2 activity by XL-844 enhanced cancer cell radiosensitivity that was associated with inhibition of DNA repair and induction of mitotic catastrophe.

2009-01-01·Molecular Cancer Therapeutics2区 · 医学

Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells

2区 · 医学

Article

作者: Palmer, Brian D. ; Maybaum, Jonathan ; Canman, Christine E. ; Parsels, Joshua D. ; Denny, William A. ; Lawrence, Theodore S. ; Morgan, Meredith A. ; Tanska, Daria M. ; Booth, R. John ; Kraker, Alan J. ; Parsels, Leslie A.

AbstractThe protein kinase checkpoint kinase 1 (Chk1) has been implicated as a key regulator of cell cycle progression and DNA repair, and inhibitors of Chk1 (e.g., UCN-01 and EXEL-9844) potentiate the cytotoxic actions of chemotherapeutic drugs in tumor cells. We have examined the ability of PD-321852, a small-molecule Chk1 inhibitor, to potentiate gemcitabine-induced clonogenic death in a panel of pancreatic cancer cell lines and evaluated the relationship between endpoints associated with Chk1 inhibition and chemosensitization. Gemcitabine chemosensitization by minimally toxic concentrations of PD-321852 ranged from minimal (<3-fold change in survival) in Panc1 cells to >30-fold in MiaPaCa2 cells. PD-321852 inhibited Chk1 in all cell lines as evidenced by stabilization of Cdc25A; in combination with gemcitabine, a synergistic loss of Chk1 protein was observed in the more sensitized cell lines. Gemcitabine chemosensitization, however, did not correlate with abrogation of the S-M or G2-M checkpoint; PD-321852 did not induce premature mitotic entry in gemcitabine-treated BxPC3 or M-Panc96 cells, which were sensitized to gemcitabine 6.2- and 4.6-fold, respectively. In the more sensitized cells lines, PD-321852 not only inhibited gemcitabine-induced Rad51 focus formation and the recovery from gemcitabine-induced replication stress, as evidenced by persistence of γ-H2AX, but also depleted these cells of Rad51 protein. Our data suggest the inhibition of this Chk1-mediated Rad51 response to gemcitabine-induced replication stress is an important factor in determining gemcitabine chemosensitization by Chk1 inhibition in pancreatic cancer cells. [Mol Cancer Ther 2009;8(1):45–54]

100 项与 XL-844 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05149

研发状态

10 条进展最快的记录,

登录

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
淋巴瘤	临床1期	美国	Exelixis, Inc.	2007-05-01
慢性淋巴细胞白血病	临床1期	美国	Exelixis, Inc.	2005-10-07
小淋巴细胞淋巴瘤	临床1期	美国	Exelixis, Inc.	2005-10-07
晚期癌症	临床前	美国	Exelixis, Inc.	2007-05-01