Ro-24-7429(Ro-24-7429) - 药物靶点：HIV-1 tat x RUNX1_在研适应症：脉络膜新生血管，伴有糖尿病的增殖性视网膜病变_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

HIV-1 tat x RUNX1

作用机制

RUNX1拮抗剂(RUNX family transcription factor 1 antagonists)、Tat (HIV)抑制剂(人类免疫缺陷病毒tat基因产品抑制剂)

治疗领域

心血管疾病内分泌与代谢疾病眼部疾病

在研适应症

脉络膜新生血管伴有糖尿病的增殖性视网膜病变

非在研适应症

艾滋病相关性卡波西肉瘤

原研机构

F. Hoffmann-La Roche Ltd.

在研机构

The Schepens Eye Research Institute, Inc.

非在研机构

Hoffmann-La Roche, Inc.

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C14H13ClN4

InChIKeyLEAKQIXYSHIHCW-UHFFFAOYSA-N

CAS号139339-45-0

关联

2

项与 Ro-24-7429 相关的临床试验

NCT00000760 / Completed临床1期IIT

A Randomized Study of Activity, Safety, and Tolerance of Oral Ro 24-7429 (Tat Antagonist) in Patients With HIV Infection

To study the anti-HIV activity of the various doses of Ro 24-7429 monotherapy based on virologic and immunologic endpoints. To study the safety and tolerance of Ro 24-7429. To explore relationships between exposure to Ro 24-7429 and its metabolites and antiviral activity and drug toxicity. To determine a safe, tolerable, and active dose regimen of Ro 24-7429, and to make preliminary observations of Ro 24-7429 in combination with another antiretroviral nucleoside.
The HIV genome contains a number of genes that regulate viral replication. Control of the activity of these genes and their encoded proteins represents a potential target for development of new antiretroviral drugs. The tat (transactivator of transcription of HIV) antagonist Ro 24-7429 is the first compound for clinical testing that utilizes this approach for therapy of HIV infection.

开始日期-

申办/合作机构

National Institute of Allergy & Infectious Diseases

[+1]

NCT00002314 / Completed临床2期

A Phase II Study of Oral Ro 24-7429 (Tat Antagonist) in Patients With HIV-Related Kaposi's Sarcoma

To study the effects of Ro 24-7429 on tumor growth in patients with HIV-related Kaposi's sarcoma. To study the safety and tolerance, effects on HIV replication, and immunologic effects of Ro 24-7429 in this patient population. To explore relationships between exposure to Ro 24-7429 and its metabolites with its antitumor and antiviral activities and drug toxicity.

开始日期-

申办/合作机构

Hoffmann-La Roche, Inc.

100 项与 Ro-24-7429 相关的临床结果

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100 项与 Ro-24-7429 相关的转化医学

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100 项与 Ro-24-7429 相关的专利（医药）

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19

项与 Ro-24-7429 相关的文献（医药）

2021-07-01·The American Journal of Pathology

Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators

Article

作者: Krasemann, Susanne ; Fitzek, Antonia ; Pedron, Julien ; Marino, Claudia ; Sepulveda-Falla, Diego ; Kim, Leo A ; Ondruschka, Benjamin ; An, Miranda ; Amarnani, Dhanesh ; Arboleda-Velasquez, Joseph F ; Lagares, David ; Liu, Paul ; Steurer, Stefan ; Ramos, Leslie ; Chmielewska, Natalia ; Bushweller, John H ; Hu, Xinyao ; Chandrahas, Anita ; Heinrich, Fabian ; Whitmore, Hannah A B ; O'Hare, Michael ; Glatzel, Markus ; Delgado-Tirado, Santiago

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-β1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.

2001-04-01·Journal of Virology2区 · 医学

Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Target Distinct Phases of Early Reverse Transcription

2区 · 医学

Article

作者: Lott, William B. ; Hooker, C. William ; Harrich, David

ABSTRACTEarly HIV-1 reverse transcription can be separated into initiation and elongation phases. Here we show, using PCR analysis of negative-strand strong-stop DNA [(−)ssDNA] synthesis in intact virus, that different reverse transcriptase (RT) inhibitors affect distinct phases of early natural endogenous reverse transcription (NERT). The effects of nevirapine on NERT were consistent with a mechanism of action including both specific and nonspecific binding events. The nonspecific component of this inhibition targeted the elongation reaction, whereas the specific effect seemed principally to be directed at very early events (initiation or the initiation-elongation switch). In contrast, foscarnet and the nucleoside analog ddATP inhibited both early and late (−)ssDNA synthesis in a similar manner. We also examined compounds that targeted other viral proteins and found that Ro24-7429 (a Tat antagonist) and rosmarinic acid (an integrase inhibitor) also directly inhibited RT. Our results indicate that NERT can be used to identify and evaluate compounds that directly target the reverse transcription complex.

1999-06-10·AIDS Research and Human Retroviruses4区 · 医学

Effect of Insulin-Like Growth Factor I on HIV Type 1 Long Terminal Repeat-Driven Chloramphenicol Acetyltransferase Expression

4区 · 医学

Article

作者: Colby-Germinario, S. P. ; Acel, A. ; Mak, J. ; Davison, K. ; Faust, E. ; Kleiman, L. ; Chandok, R. ; Germinario, Ralph J. ; Wainberg, M. A.

In this study, we have investigated the ability of insulin-like growth factor I (IGF-I) to inhibit HIV long terminal repeat (LTR)-driven gene expression. Using COS 7 cells cotransfected with tat and an HIV LTR linked to a chloramphenicol acetyltransferase (CAT) reporter, we observed that physiological levels of IGF-I (10(-9) M) significantly inhibited CAT expression in a concentration- and time-dependent manner. IGF-I did not inhibit CAT expression in COS 7 cells transfected with pSVCAT, and did not affect CAT expression in the absence of cotransfection with tat. Transfection of HIV-1 proviral DNA into COS 7 cells +/- IGF-I resulted in a significant decrease (p < 0.05) in infectious virion production. Both IGF-I and Ro24-7429 inhibited LTR-driven CAT expression, while TNF-alpha-enhanced CAT expression was not affected by IGF-I. On the other hand, a plasmid encoding parathyroid hormone-related peptide exhibited dramatic additivity of inhibition of CAT expression in COS 7 cells. Finally, we show that in Jurkat or U937 cells cotransfected with HIVLTRCAT/tat, IGF-I significantly inhibited CAT expression. Further, interleukin 4 showed in U937 cells inhibition of CAT expression that was not additive to IGF-I induced inhibition. Our data demonstrate that IGF-I can specifically inhibit HIVLTRCAT expression. This inhibition may occur at the level of the tat/TAR interaction. Finally, this IGF-I effect is seen in target cell lines and similar paths of inhibition may be involved in the various cell types employed.

100 项与 Ro-24-7429 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16062

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
艾滋病相关性卡波西肉瘤	临床3期	美国	Hoffmann-La Roche, Inc.	2001-08-31
脉络膜新生血管	临床前	美国	The Schepens Eye Research Institute, Inc.	2022-05-01
伴有糖尿病的增殖性视网膜病变	临床前	美国	The Schepens Eye Research Institute, Inc.	2022-05-01