Delving into the Latest Updates on SAR-405838 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

MDM2

Mechanism

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

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Advanced cancerNeoplasms

Originator Organization

Sanofi

Active Organization-

Inactive Organization

Sanofi SA

Sanofi

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC29H34Cl2FN3O3

InChIKeyIDKAKZRYYDCJDU-HEVVSWJASA-N

CAS Registry1303607-07-9

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 SA

[+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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29

Literatures (Medical) associated with SAR-405838

15 Jan 2022·Clinical Cancer ResearchQ1 · MEDICINE

Correction: SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma

Q1 · MEDICINE

Article

Author: Lazar, Alexander J. ; Garnett, Jeannine ; Lopez, Gonzalo ; Debussche, Laurent ; Braggio, Danielle ; Dina, Lev ; Pollock, Raphael E. ; Bolshakov, Svetlana ; Meaux, Isabelle ; Ma, XiaoYen ; Creighton, Chad J. ; Prudner, Bethany C. ; Casadei, Lucia ; Bid, Hemant ; Zewdu, Abbie ; Barriere, Cedric ; Bill, Kate Lynn J.

01 Jul 2020·Acta Pharmaceutica Sinica BQ1 · CHEMISTRY

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

Q1 · CHEMISTRY

ReviewOA

Author: Fang, Yuan ; Yu, Bin ; Liao, Guochao

Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers. Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure-activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions.

01 Mar 2020·Materials Science and Engineering: CQ2 · ENGINEERING & TECHNOLOGY

A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance

Q2 · ENGINEERING & TECHNOLOGY

Article

Author: Ge, Junliang ; Zhang, Yu ; Xu, Yurui ; Zhang, Lei ; Sun, Lei ; Chen, Jianmei ; Shan, Xue ; Ning, Xinghai ; Zhang, Jikang ; Zhou, Anwei ; Gao, Ya ; Liu, Xiaoxuan ; Guo, Leilei ; An, Xueying

Drug resistance is a major hindrance in the anticancer treatment, which encourages the development of effective therapeutic strategies. For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 inhibitor MI-773, thereby improving anticancer effects. Therefore, a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) were developed for recovering p53-mediated DOX resistance in hepatocellular carcinoma. LipD/M@CMCS were composed of cationic liposomes covered with carboxymethyl chitosan (pI = 6.8), and were stable in the physiological condition (pH 7.4), but rapidly converted to cationic liposomes in tumor acidic microenvironment (pH 6.5), endowing them with tumor specificity and enhanced cellular uptake. We showed that LipD/M@CMCS could not only effectively induce cell apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors.

100 Deals associated with SAR-405838

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12541

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	FR	Sanofi SA	01 Nov 2013
Neoplasms	Phase 1	NL	Sanofi SA	01 Nov 2013
Advanced cancer	Phase 1	NL	Sanofi	13 Jul 2012
Advanced cancer	Phase 1	FR	Sanofi	13 Jul 2012
Advanced cancer	Phase 1	US	Sanofi	13 Jul 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01985191 (Pubmed \| Med J Aust) Manual	Phase 1	Advanced Malignant Solid Neoplasm	26	SAR405838+pimasertib	(ajdzxlwlww) = SAR405838 200 mg QD plus pimasertib 45 mg BID xecorcszeb (eptbcabvxg ) View more	Positive	01 Feb 2019
NCT01636479 (Pubmed \| Eur J Cancer Care (Engl))	Phase 1	Neoplasms \| Advanced cancer	77	SAR405838	(eipjnslbov) = ygltlirubv labioggmqu (davgopzmgy )	-	01 May 2017