Delving into the Latest Updates on RG-7112 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [2]

Target

MDM2

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.

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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49

Literatures (Medical) associated with RG-7112

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

01 Apr 2024·Frontiers of Medicine

Multi-omics joint analysis revealed the metabolic profile of retroperitoneal liposarcoma

Article

Author: Niu, Yujia ; Ren, Yantao ; Zhang, Quan ; Wang, Yue ; Xi, Zhe ; Zhuang, Aobo ; Chen, Xiaobing ; Xie, Fu'an ; Yan, Guangting ; Qin, Dongmei ; Zheng, Zhigang ; Lin, Shu-Hai ; Yang, Kunrong ; Wu, Ting ; Li, Peng ; Lian, Lanlan ; Li, Xi ; Luo, Chenghua ; Xia, Xiaogang ; Xiao, Mengmeng ; Zhang, Gen ; Li, Wengang ; Gu, Lingwei

Retroperitoneal liposarcoma (RLPS) is the main subtype of retroperitoneal soft sarcoma (RSTS) and has a poor prognosis and few treatment options, except for surgery. The proteomic and metabolic profiles of RLPS have remained unclear. The aim of our study was to reveal the metabolic profile of RLPS. Here, we performed proteomic analysis (n = 10), metabolomic analysis (n = 51), and lipidomic analysis (n = 50) of retroperitoneal dedifferentiated liposarcoma (RDDLPS) and retroperitoneal well-differentiated liposarcoma (RWDLPS) tissue and paired adjacent adipose tissue obtained during surgery. Data analysis mainly revealed that glycolysis, purine metabolism, pyrimidine metabolism and phospholipid formation were upregulated in both RDDLPS and RWDLPS tissue compared with the adjacent adipose tissue, whereas the tricarboxylic acid (TCA) cycle, lipid absorption and synthesis, fatty acid degradation and biosynthesis, as well as glycine, serine, and threonine metabolism were downregulated. Of particular importance, the glycolytic inhibitor 2-deoxy-D-glucose and pentose phosphate pathway (PPP) inhibitor RRX-001 significantly promoted the antitumor effects of the MDM2 inhibitor RG7112 and CDK4 inhibitor abemaciclib. Our study not only describes the metabolic profiles of RDDLPS and RWDLPS, but also offers potential therapeutic targets and strategies for RLPS.

30 Aug 2023·Cancers

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells.

Article

Author: Togashi, Keita ; Okada, Masashi ; Mitobe, Yuta ; Kitanaka, Chifumi ; Sonoda, Yukihiko ; Sugai, Asuka ; Nakagawa-Saito, Yurika ; Suzuki, Shuhei

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 on inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2-p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2's interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells.

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
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 1	US	Hoffmann-La Roche, Inc.	01 May 2008
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 1	CA	Hoffmann-La Roche, Inc.	01 May 2008
Small Lymphocytic Lymphoma	Phase 1	IT	Hoffmann-La Roche, Inc.	01 May 2008
Small Lymphocytic Lymphoma	Phase 1	US	Hoffmann-La Roche, Inc.	01 May 2008
Small Lymphocytic Lymphoma	Phase 1	CA	Hoffmann-La Roche, Inc.	01 May 2008
Small Lymphocytic Lymphoma	Phase 1	GB	Hoffmann-La Roche, Inc.	01 May 2008
Advanced cancer	Phase 1	US	Hoffmann-La Roche, Inc.	01 Dec 2007
Advanced cancer	Phase 1	FR	Hoffmann-La Roche, Inc.	01 Dec 2007
Advanced Malignant Solid Neoplasm	Phase 1	FR	Hoffmann-La Roche, Inc.	01 Dec 2007
Advanced Malignant Solid Neoplasm	Phase 1	US	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	(dfniaddzst) = Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia hizpjrnuxt (pdbmwqdzon ) View more	-	20 May 2012