Delving into the Latest Updates on RG-7112 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [2]

Target

MDM2

Action

inhibitors

Mechanism

MDM2 inhibitors(p53-binding protein Mdm-2 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesCongenital Disorders+ [2]

Active Indication-

Inactive Indication

Acute Lymphoblastic LeukemiaAcute Myeloid LeukemiaAdvanced cancer+ [8]

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization-

Inactive Organization

Hoffmann-La Roche, Inc.

License Organization-

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC38H48Cl2N4O4S

InChIKeyQBGKPEROWUKSBK-QPPIDDCLSA-N

CAS Registry939981-39-2

This open-label, extension study is designed to provide continuing treatment with RO5045337 to participants who have completed parent studies NO21279 (NCT00623870), NO21280 (NCT00559533), NP25299 (NCT01164033), NP28021 (NCT01605526) or NP28023 (NCT01635296). Participants are eligible to participate in this study if they have completed required Phase 1 study assessments for primary objectives of respective parent protocol and are having evidence of clinical benefit (as defined by the parent protocol). Participants will continue the most similar dose and formulation available (which does not exceed the maximum tolerated dose [MTD] or the maximum safely administered dose for that formulation during Phase 1) and the same schedule of RO5045337 treatment that they were receiving at the time of transitioning from the parent clinical study protocol.

Start Date28 Nov 2012

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

NCT01635296

/ CompletedPhase 1

A Multicenter, Open Label, Phase 1B Study of Escalating Doses of RO5045337 Administered Orally, With Cytarabine Administered A) Subcutaneously, or B) Intravenously, in Patients With Acute Myelogenous Leukemia (AML)

This multi-center, open-label, Phase 1b study will evaluate the safety, pharmacokinetics and efficacy of RO5045337 in combination with cytarabine in patients with acute myelogenous leukemia. In Arm A, cohorts of previously untreated patients deemed unsuitable for standard induction therapy will receive escalating oral doses of RO5045377 and cytarabine 20 mg/m2 subcutaneously daily for Days 1 to 10 of each 28-day cycle. In Arm B, cohorts of patients who have relapsed or are refractory after at least one cytarabine/anthracycline containing regimen will receive escalating oral doses of RO5045377 on Days 1 to 5 and cytarabine 1 gm/m2 intravenously on Days 1 to 6 of each 28-day cycle. Patients will receive up to 4 cycles of therapy, patients in Arm A who achieve hematologic response may continue additional cycles until disease progression.

Start Date01 Jul 2012

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

NCT01605526

/ CompletedPhase 1

A Multi-center, Open-label Phase IB Study of Escalating Doses of RO5045337, an Oral Small Molecule MDM2 Antagonist, in Combination With Doxorubicin in Patients With Soft Tissue Sarcoma

This multicenter, open-label, Phase 1b study will evaluate the safety, pharmacokinetics and efficacy of RO5045337 in combination with doxorubicin in patients with soft tissue sarcoma. Cohorts of patients will receive escalating doses of RO5045337 orally on Days 1-5 (1-3) of each 28-day cycle in combination with doxorubicin 60 mg/m2 intravenously on Day 1 of each cycle for up to 6 cycles.

Start Date01 May 2012

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with RG-7112

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100 Translational Medicine associated with RG-7112

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100 Patents (Medical) associated with RG-7112

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95

Literatures (Medical) associated with RG-7112

14 Mar 2025·Science Advances

Senolytic treatment for low back pain

Article

Author: Lee, Seunghwan ; Millecamps, Magali ; Martinez, Oliver Wu ; Sheng, Kai ; Gilbert, Alice ; Mannarino, Matthew ; Ouellet, Jean A. ; Ghazizadeh, Saber ; Peirs, Cedric ; Cherif, Hosni ; Cousineau, Elsa ; Naeini, Reza Sharif ; S. Stone, Laura ; Gao, Chan ; Haglund, Lisbet

Senescent cells (SnCs) accumulate because of aging and external cellular stress throughout the body. They adopt a senescence-associated secretory phenotype (SASP) and release inflammatory and degenerative factors that actively contribute to age-related diseases, such as low back pain (LBP). The senolytics, o -vanillin and RG-7112, remove SnCs in human intervertebral discs (IVDs) and reduce SASP release, but it is unknown whether they can treat LBP. sparc −/− mice, with LBP, were treated orally with o -vanillin and RG-7112 as single or combination treatments. Treatment reduced LBP and SASP factor release and removed SnCs from the IVD and spinal cord. Treatment also lowered degeneration scores in the IVDs, improved vertebral bone quality, and reduced the expression of pain markers in the spinal cord. Together, our data suggest RG-7112 and o -vanillin as potential disease-modifying drugs for LBP and other painful disorders linked to cell senescence.

01 Jan 2025·Journal of Pharmaceutical Analysis

Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione

Article

Author: Yang, Kunrong ; Yu, Chundong ; Chen, Kun ; Yan, Guangting ; Qin, Dongmei ; Xiao, Mengmeng ; Chen, Xiaobing ; Li, Wengang ; Li, Xi ; Wu, Ting ; Yang, Chunkang ; Lian, Lanlan ; Luo, Chenghua ; Lin, Shu-Hai ; Xie, Fu'an ; Zhang, Quan ; Zhuang, Aobo ; Zhang, Ruyi ; Shen, Ye ; Xia, Xiaogang ; Niu, Yujia ; Kong, Xu

Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [¹⁵N₂]-cystine and [¹³C₅]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.

01 Oct 2024·Apoptosis

Strong activation of p53 by actinomycin D and nutlin-3a overcomes the resistance of cancer cells to the pro-apoptotic activity of the FAS ligand

Article

Author: Głowala-Kosińska, Magdalena ; Gdowicz-Kłosok, Agnieszka ; Łasut-Szyszka, Barbara ; Rusin, Marek ; Będzińska, Agnieszka ; Krześniak, Małgorzata

AbstractThe FAS ligand (FASLG) is expressed on lymphocytes, which employ it to activate death receptors on target cells. Cancer cells are generally resistant to apoptosis triggered by FASLG. In this work, we found a way to circumvent this resistance by treatment with actinomycin D (ActD) and nutlin-3a (Nut3a). We selected this drug combination based on our transcriptomic data showing strong activation of proapoptotic genes, including those for receptor-mediated apoptosis, in cells exposed to actinomycin D and nutlin-3a. To test our hypothesis, we pre-exposed cancer cell lines to this drug combination for 45 h and then treated them with recombinant FASLG. This almost instantaneously killed most cells. Actinomycin D and nutlin-3a strongly cooperated in the sensitization because the effect of the drugs acting solo was not as spectacular as the drug combination, which together with FASLG killed more than 99% of cells. Based on the caspase activation pattern (caspase-8, caspase-9, caspase-10), we conclude that both extrinsic and intrinsic pro-apoptotic pathways were engaged. In engineered p53-deficient cells, this pro-apoptotic effect was completely abrogated. Therefore, the combination of ActD + Nut3a activates p53 in an extraordinary way, which overcomes the resistance of cancer cells to apoptosis triggered by FASLG. Interestingly, other combinations of drugs, e.g., etoposide + nutlin-3a, actinomycin D + RG7112, and actinomycin D + idasanutlin had a similar effect. Moreover, normal human fibroblasts are less sensitive to death induced by ActD + Nut3a + FASLG. Our findings create the opportunity to revive the abandoned attempts of cancer immunotherapy employing the recombinant FAS ligand.Graphical Abstract

100 Deals associated with RG-7112

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14793

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic lymphocytic leukaemia refractory	Phase 1	United States	Hoffmann-La Roche, Inc.	01 May 2008
Chronic lymphocytic leukaemia refractory	Phase 1	United Kingdom	Hoffmann-La Roche, Inc.	01 May 2008
Chronic lymphocytic leukaemia refractory	Phase 1	Italy	Hoffmann-La Roche, Inc.	01 May 2008
Chronic lymphocytic leukaemia refractory	Phase 1	Canada	Hoffmann-La Roche, Inc.	01 May 2008
Small Lymphocytic Lymphoma	Phase 1	United Kingdom	Hoffmann-La Roche, Inc.	01 May 2008
Small Lymphocytic Lymphoma	Phase 1	United States	Hoffmann-La Roche, Inc.	01 May 2008
Advanced cancer	Phase 1	United States	Hoffmann-La Roche, Inc.	01 Dec 2007
Advanced cancer	Phase 1	France	Hoffmann-La Roche, Inc.	01 Dec 2007
Advanced Malignant Solid Neoplasm	Phase 1	France	Hoffmann-La Roche, Inc.	01 Dec 2007
Advanced Malignant Solid Neoplasm	Phase 1	United States	Hoffmann-La Roche, Inc.	01 Dec 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2012	Phase 1	Solid tumor	106	RG7112	(zudlwpzbby) = Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia zqfdkecgll (dqyenwieds ) View more	-	20 May 2012