Delving into the Latest Updates on Milademetan Tosylate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target-

Action-

Mechanism-

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication

Refractory acute myeloid leukemiaRelapsing acute myeloid leukemia

Originator Organization

Rain Oncology, Inc.

Active Organization

Rain Oncology, Inc.

Inactive Organization

The University of Texas MD Anderson Cancer Center

License Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC37H42Cl2FN5O7S

InChIKeyNHIUKVHKLJSJEA-LINJWFRASA-N

CAS Registry1398569-75-9

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.

Start Date17 Dec 2018

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

[+1]

100 Clinical Results associated with Milademetan Tosylate

Login to view more data

100 Translational Medicine associated with Milademetan Tosylate

Login to view more data

100 Patents (Medical) associated with Milademetan Tosylate

Login to view more data

9

Literatures (Medical) associated with Milademetan Tosylate

28 Apr 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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.

01 Feb 2021·Molecular Cancer ResearchQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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.

01 Oct 2020·Cancer ScienceQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: 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 Deals associated with Milademetan Tosylate

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Refractory acute myeloid leukemia	Phase 1	United States	The University of Texas MD Anderson Cancer Center	17 Dec 2018
Relapsing acute myeloid leukemia	Phase 1	United States	The University of Texas MD Anderson Cancer Center	17 Dec 2018
Neoplasms	Discovery	-	Rain Oncology, Inc.	-

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03634228 (Phase I study of Milademetan (DS3032b), CTgov)	Phase 1/2	Relapsing acute myeloid leukemia \| Refractory acute myeloid leukemia	16	Cytarabine+Milademetan Tosylate	(gzsaimwhgb) = nrshjjdunu udddqeqrkr (cacyehdlfn, gtzyoqwrbo - lndibqcpal)	-	15 Jun 2023