Milademetan Tosylate(Milademetan Tosylate) - 在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点-

作用方式-

作用机制-

治疗领域

肿瘤

在研适应症

肿瘤

非在研适应症

难治性急性髓细胞白血病复发性急性髓细胞白血病

原研机构

Rain Oncology, Inc.

在研机构

Rain Oncology, Inc.

非在研机构

The University of Texas MD Anderson Cancer Center

权益机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C37H42Cl2FN5O7S

InChIKeyNHIUKVHKLJSJEA-LINJWFRASA-N

CAS号1398569-75-9

关联

1

项与 Milademetan Tosylate 相关的临床试验

NCT03634228

/ Terminated临床1/2期IIT

A Phase I/II Study of the Oral MDM2 Inhibitor DS-3032b (Milademetan) in Combination With Low Dose Cytarabine (LDAC) in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML)

This phase I/II trial studies the side effects and best dose of milademetan tosylate and to see how well it works with cytarabine with or without ventoclax in treating participants with acute myeloid leukemia that has come back (recurrent) or that does not respond to treatment (refractory). Milademetan tosylate and ventoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known if giving milademetan tosylate and low-dose cytarabine with or without ventoclax will work better in treating participants with recurrent or refractory acute myeloid leukemia.

开始日期2018-12-17

申办/合作机构

The University of Texas MD Anderson Cancer Center

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100 项与 Milademetan Tosylate 相关的临床结果

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100 项与 Milademetan Tosylate 相关的转化医学

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100 项与 Milademetan Tosylate 相关的专利（医药）

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9

项与 Milademetan Tosylate 相关的文献（医药）

2022-04-28·Journal of Medicinal Chemistry1区 · 医学

Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells

1区 · 医学

Article

作者: Yan, Ziqin ; Meng, Xiangjing ; Zhang, Daizhou ; Zhang, Shiyan ; Lyu, Xilin ; Li, Yafang ; Gong, Yang ; Zhao, Yujun ; Lou, Jianfeng

Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding K_i values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53-targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells.

2021-02-01·Molecular Cancer Research2区 · 医学

Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents

2区 · 医学

Article

作者: van Krieken, J. Han ; Bhagat, Govind ; Dybkaer, Karen ; You, Hua ; Hsi, Eric D. ; Wang, Xudong ; Tam, Wayne ; Parsons, Benjamin M. ; Liu, Phillip ; Xu-Monette, Zijun Y. ; Deng, Manman ; Piris, Miguel A. ; Xu, Bing ; Ferreri, Andrés J.M. ; Fang, Xiaosheng ; Huh, Jooryung ; Young, Ken H. ; Ponzoni, Maurilio ; Visco, Carlo ; Zu, Youli ; Chiu, April ; Hagemeister, Fredrick ; Winter, Jane N. ; Pham, Lan V. ; Møller, Michael B. ; Li, Yong ; Zhu, Feng ; Tzankov, Alexandar

AbstractDiffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2–targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies.Implications:The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.Visual Overview:http://mcr.aacrjournals.org.libproxy1.nus.edu.sg/content/molcanres/19/2/249/F1.large.jpg.

2020-10-01·Cancer Science2区 · 医学

Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

2区 · 医学

ArticleOA

作者: Tanikawa, Michihiro ; Wada‐Hiraike, Osamu ; Kojima, Machiko ; Fujii, Tomoyuki ; Nagasaka, Kazunori ; Takeuchi, Makoto ; Oki, Shinya ; Osuga, Yutaka ; Makii, Chinami ; Taguchi, Ayumi ; Matsumoto, Yoko ; Sone, Kenbun ; Oda, Katsutoshi ; Kawata, Yoshiko ; Hiraike, Haruko ; Miyagawa, Yuko ; Ayabe, Takuya ; Honjo, Harunori

AbstractAdvanced clear cell carcinomas originating from both ovaries and kidneys with cancerous peritonitis have poor prognoses. Murine double‐minute 2 (MDM2) is a potential therapeutic target for clear cell ovarian carcinomas with WT TP53. Herein, we characterized the antiangiogenic and antitumor effects of the MDM2 inhibitors DS‐3032b and DS‐5272 in 6 clear cell ovarian carcinoma cell lines and 2 clear cell renal carcinoma cell lines, as well as in clear cell ovarian carcinomas s.c. xenograft and ID8 (murine ovarian cancer cells with WT TP53) cancer peritonitis mouse models. In clear cell ovarian carcinoma s.c. xenograft mouse models, DS‐3032b significantly reduced WT TP53 clear cell ovarian carcinoma‐ and clear cell renal carcinoma‐derived tumor volumes. In ID8 mouse models, DS‐5272 significantly inhibited ascites production, reduced body weight, and significantly improved overall survival. Additionally, DS‐5272 reduced the tumor burden of peritoneal dissemination and decreased CD31+ cells in a dose‐dependent manner. Furthermore, DS‐5272 significantly decreased vascular endothelial growth factor concentrations in both sera and ascites. Combined therapy with MDM2 inhibitors and everolimus showed synergistic, and dose‐reduction potential, for clear cell carcinoma treatment. Our findings suggest that MDM2 inhibitors represent promising molecular targeted therapy for clear cell carcinomas, thereby warranting further studies to evaluate the efficacy and safety of dual MDM2/mTOR inhibitors in clear cell carcinoma patients.

100 项与 Milademetan Tosylate 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
难治性急性髓细胞白血病	临床1期	美国	The University of Texas MD Anderson Cancer Center	2018-12-17
复发性急性髓细胞白血病	临床1期	美国	The University of Texas MD Anderson Cancer Center	2018-12-17
肿瘤	药物发现	-	Rain Oncology, Inc.	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03634228 (Phase I study of Milademetan (DS3032b), CTgov)	临床1/2期	复发性急性髓细胞白血病 \| 难治性急性髓细胞白血病	16	Cytarabine+Milademetan Tosylate	(鬱構膚鹽觸醖醖鏇構艱) = 壓鹹築鹽範範衊繭網範襯廠衊鬱鬱壓遞願顧鏇 (願壓夢範餘衊繭觸網壓, 衊積憲壓網醖齋壓獵淵 ~ 餘糧願簾鏇憲製衊選製)	-	2023-06-15