Delving into the Latest Updates on SAR-405838 with Synapse

Primary Objectives:
To determine the recommended Phase 2 dose of SAR405838 / pimasertib combination therapy in patients with solid tumors.
To assess the anti-tumor activities of SAR405838 / pimasertib in patients with solid tumors.
Secondary Objectives:
To characterize the pharmacokinetic profile of SAR405838 and pimasertib.
To evaluate the pharmacodynamic effect of the SAR405838 and pimasertib.
To characterize genetic status in tumor tissue and circulating tumor DNA.

Start Date01 Nov 2013

Sponsor / Collaborator

Sanofi

[+1]

NCT01636479

/ CompletedPhase 1

A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Biological Activity of SAR405838 in Patients With Advanced Cancer

Primary Objectives:
To determine safety and the maximum tolerated dose (MTD) of SAR405838 through the characterization of dose-limiting toxicities (DLTs).
To assess biological activities in patients with dedifferentiated liposarcoma during MTD cohort expansion.
Secondary Objectives:
Pharmacokinetic (PK) profile of SAR405838.
Biomarkers in association with SAR405838.
Anti-tumor activity in response to SAR405838.
Food effect on SAR405838 PK.
Compliance with SAR405838 treatment.
Cytochrome P450 3A4/5 (CYP3A4/5) activity.

Start Date13 Jul 2012

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with SAR-405838

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100 Translational Medicine associated with SAR-405838

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100 Patents (Medical) associated with SAR-405838

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44

Literatures (Medical) associated with SAR-405838

01 Mar 2023·Cellular and Molecular Life Sciences

Network-informed discovery of multidrug combinations for ERα+/HER2-/PI3Kα-mutant breast cancer

Article

Author: Zoetemelk, Marloes ; Picard, Didier ; Nowak-Sliwinska, Patrycja ; Hany, Dina ; Bhattacharya, Kaushik

AbstractBreast cancer is a persistent threat to women worldwide. A large proportion of breast cancers are dependent on the estrogen receptor α (ERα) for tumor progression. Therefore, targeting ERα with antagonists, such as tamoxifen, or estrogen deprivation by aromatase inhibitors remain standard therapies for ERα + breast cancer. The clinical benefits of monotherapy are often counterbalanced by off-target toxicity and development of resistance. Combinations of more than two drugs might be of great therapeutic value to prevent resistance, and to reduce doses, and hence, decrease toxicity. We mined data from the literature and public repositories to construct a network of potential drug targets for synergistic multidrug combinations. With 9 drugs, we performed a phenotypic combinatorial screen with ERα + breast cancer cell lines. We identified two optimized low-dose combinations of 3 and 4 drugs of high therapeutic relevance to the frequent ERα + /HER2-/PI3Kα-mutant subtype of breast cancer. The 3-drug combination targets ERα in combination with PI3Kα and cyclin-dependent kinase inhibitor 1 (p21). In addition, the 4-drug combination contains an inhibitor for poly (ADP-ribose) polymerase 1 (PARP1), which showed benefits in long-term treatments. Moreover, we validated the efficacy of the combinations in tamoxifen-resistant cell lines, patient-derived organoids, and xenograft experiments. Thus, we propose multidrug combinations that have the potential to overcome the standard issues of current monotherapies.

01 Nov 2022·Clinical Cancer Research

p53 Inhibits Bmi-1-driven Self-Renewal and Defines Salivary Gland Cancer Stemness

Article

Author: Yoon, Eusik ; Wicha, Max S. ; Warner, Kristy A. ; Zhang, Zhixiong ; Nör, Jacques E. ; Zhang, Zhaocheng ; Herzog, Alexandra E. ; Mantesso, Andrea ; Wang, Shaomeng ; Rodriguez-Ramirez, Christie

AbstractPurpose:Mucoepidermoid carcinoma (MEC) is a poorly understood salivary gland malignancy with limited therapeutic options. Cancer stem cells (CSC) are considered drivers of cancer progression by mediating tumor recurrence and metastasis. We have shown that clinically relevant small molecule inhibitors of MDM2–p53 interaction activate p53 signaling and reduce the fraction of CSC in MEC. Here we examined the functional role of p53 in the plasticity and self-renewal of MEC CSC.Experimental Design:Using gene silencing and therapeutic activation of p53, we analyzed the cell-cycle profiles and apoptosis levels of CSCs in MEC cell lines (UM-HMC-1, -3A, -3B) via flow cytometry and looked at the effects on survival/self-renewal of the CSCs through sphere assays. We evaluated the effect of p53 on tumor development (N = 51) and disease recurrence (N = 17) using in vivo subcutaneous and orthotopic murine models of MEC. Recurrence was followed for 250 days after tumor resection.Results:Although p53 activation does not induce MEC CSC apoptosis, it reduces stemness properties such as self-renewal by regulating Bmi-1 expression and driving CSC towards differentiation. In contrast, downregulation of p53 causes expansion of the CSC population while promoting tumor growth. Remarkably, therapeutic activation of p53 prevented CSC-mediated tumor recurrence in preclinical trials.Conclusions:Collectively, these results demonstrate that p53 defines the stemness of MEC and suggest that therapeutic activation of p53 might have clinical utility in patients with salivary gland MEC.

20 Oct 2022·ChemistrySelect

Identifying Potential p53‐MDM2 Interaction Antagonists: An Integrated Approach of Pharmacophore‐Based Virtual Screening, Interaction Fingerprinting, MD Simulation and DFT Studies

Author: Yekeen, Abeeb Abiodun ; Idris, Mukhtar Oluwaseun ; Fadahunsi, Adeola Abraham ; Alakanse, Suleiman Oluwaseun ; Durojaye, Olanrewaju Ayodeji ; Sedzro, Divine Mensah

AbstractThe inactivation of p53 in tumor cells is as a result of the deletion or mutation of the TP3 gene, while the inhibition of its activity is by interaction with overexpressed mouse double minute 2 (MDM2). Small‐molecule inhibitors that target the interaction between p53 and MDM2 are now being pursued as potential therapeutic agents for cancer therapy. To date, many small‐molecule inhibitors of the p53‐MDM2 interaction have been identified which, however, possess toxicity, bioavailability and/or drug resistance limitations. In this study, we directed a ligand‐based pharmacophore modeling protocol towards the search of novel inhibitors of the p53‐MDM2 interaction. Generated pharmacophore features from known and novel inhibitors of the p53‐MDM2 interaction were used in searching the ZINC database for drug‐like molecules. With stringent search parameters set, we generated a ligand library of 7000 ZINC compounds and a sub‐library of 907 compounds from the Selleckchem's “Apoptosis Compound Library”. Upon the docking of both compound libraries to the target receptor, the resulting top 100 binders were subjected to in silico ADMET screening, out of which the top 3 compounds with the most favorable properties (ZINC71932671, ZINC02375540 and ZINC08870467) were selected for further assessment. These 3 hits also displayed favorable interactions with important residues involved in the p53‐MDM2 protein‐protein interaction, while the molecular dynamics simulation study suggest a stable conformation for the protein‐ligand complexes. These three compounds can be used in the development of potential cancer therapeutics that are targeted at restoring the function of p53 by blocking its interaction with MDM2.

100 Deals associated with SAR-405838

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External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Malignant Pleural Mesothelioma	Preclinical	Japan	Saitama Medical University International Medical Center	22 Mar 2024
Solid tumor	Preclinical	Netherlands	Sanofi	01 Nov 2013
Solid tumor	Preclinical	France	Sanofi	01 Nov 2013
Advanced cancer	Preclinical	Netherlands	Sanofi	13 Jul 2012
Advanced cancer	Preclinical	France	Sanofi	13 Jul 2012
Advanced cancer	Preclinical	United States	Sanofi	13 Jul 2012

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Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01985191 (Pubmed \| Med J Aust \| Br J Cancer) Manual	Phase 1	Advanced Malignant Solid Neoplasm	26	SAR405838+pimasertib	(pusliftcse) = SAR405838 200 mg QD plus pimasertib 45 mg BID zyzlgxjirt (sqygsteoyt ) View more	Positive	01 Feb 2019
NCT01636479 (Pubmed \| Eur J Cancer)	Phase 1	Advanced cancer TP53 mutation \| TP53 wild-type \| HDM2 amplification	-	SAR405838	(yyqglxcvmu) = lwpkxlgxpq lznrhacqhx (tudizobaex )	-	01 May 2017