Delving into the Latest Updates on Salirasib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

S-Farnesylthiosalicyclic acid, Salirasib (INN/USAN), Transfarnesylthiosalicyclic acid

+ [3]

Target

RAS

Mechanism

RAS inhibitors(RAS type GTPase family inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication-

Inactive Indication

Advanced Lung Non-Small Cell CarcinomaColorectal CancerNon-Small Cell Lung Cancer+ [2]

Originator Organization

Concordia Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Ono Pharmaceutical Co., Ltd.Kadmon Pharmaceuticals LLCConcordia Pharmaceuticals, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC22H30O2S

InChIKeyWUILNKCFCLNXOK-CFBAGHHKSA-N

CAS Registry162520-00-5

AbstractHeterogeneous nuclear ribonucleoprotein U (hnRNPU) is known to play multiple biological roles by regulating transcriptional expression, RNA splicing, RNA stability, and chromatin structure in a tissue‐dependent manner. The role of hnRNPU in skeletal muscle development and maintenance has not been previously evaluated. In this study, skeletal muscle specific hnRNPU knock out mice is utilized and evaluated skeletal muscle mass and immune cell infiltration through development. By 4 weeks, muscle‐specific hnRNPU knockout mice revealed Ly6C+ monocyte infiltration into skeletal muscle, which preceded muscle atrophy. Canonical NF‐kB signaling is activated in a myofiber‐autonomous manner with hnRNPU repression. Inducible hnRNPU skeletal muscle knockout mice further demonstrated that deletion of hnRNPU in adulthood is sufficient to cause muscle atrophy, suggesting that hnRNPU's role in muscle maintenance is not during development alone. Treatment with salirasib, to inhibit proliferation of immune cells, prevents muscle atrophy in muscle‐specific hnRNPU knock out mice, indicating that immune cell infiltration plays causal role in muscle atrophy of hnRNPU knock out mice. Overall, the findings suggest that loss of hnRNPU triggers muscle inflammation and activates NF‐κB signaling in a cell‐autonomous manner, culminating in muscle atrophy.

01 Feb 2024·Theriogenology

Heat stress induces ferroptosis of porcine Sertoli cells by enhancing CYP2C9-Ras- JNK axis

Article

Author: XianZhong, Wang ; Yang, Huan ; Qiu, MeiJia ; Xue, HongYan ; Zhang, JiaoJiao ; Yang, Weirong ; Cai, XiaQing ; Deng, ChengChen

Heat stress leads to the accumulation of lipid peroxides in Sertoli cells. Unrestricted lipid peroxidation of catalyzed polyunsaturated fatty acids by Cytochrome P450 (CYP) drive the ferroptosis. However, little is known about the role of CYP cyclooxygenase in heat stress-induced ferroptosis in Sertoli cells. In this study, we investigated the relationship between CYP cyclooxygenase and heat stress-induced ferroptosis in porcine Sertoli cells, as well as whether Ras-JNK signaling is involved in the process. The results showed that heat stress significantly increased the expression of cytochrome P450 cyclooxygenase 2C9 (CYP2C9) and the content of epoxyeicosatrienoic acids (EETs), although there are no significant effect on the expression of cytochrome P450 cyclooxygenase 2J2 (CYP2J2) and cytochrome P450 cyclooxygenase 2C8 (CYP2C8). In addition, heat stress reduced the cell viability, the protein expression level of glutathione peroxidase 4 (GPX4) and Ferritin (all P < 0.01) while increased the level of intracellular reactive oxygen species (ROS) and the protein level of Transferrin receptor 1(TFR1) (both P < 0.01), as well as activating the Ras-JNK signaling pathway. Ferrostatin-1, a ferroptosis-specific inhibitor, reduced ROS levels and the protein level of TFR1 (both P < 0.01), but elevated the cell viability, the protein level of GPX4, and Ferritin (all P < 0.01). Sulfaphenazole, a specific inhibitor of CYP2C9 or two small interfering RNAs targaring CYP2C9 enhanced the cell viability (all P < 0.01), while reduced the content of EETs (all P < 0.01) and inhibited the Ras-JNK signaling and ferroptosis under heat stress. Salirasib, a specific inhibitor of Ras, significantly elevated the cell viability, whereas reduced the level of intracellular ROS and inhibited the phosphorylation of JNK, and alleviated heat stress-induced ferroptosis in porcine Sertoli cells. Notably, there is no effect on the expression of CYP2C9 and the content of EETs. These results indicate that heat stress can induce ferroptosis in Sertoli cells by increasing the expression of CYP2C9 and the content of EETs, which in true activates the Ras-JNK signaling pathway, but there is no feedback from Ras-JNK signaling to the expression of CYP2C9. Our study finds a novel heat stress-induced cell death model of Sertoli cells as well as providing the therapeutic potential for anti-ferroptosis.

01 Sep 2023·Bioorganic & Medicinal Chemistry

Lipophilic modification of salirasib modulates the antiproliferative and antimigratory activity

Article

Author: Padrón, José M ; Zalazar, Evelyn Arel ; Girardini, Javier E ; Etichetti, Carla M Borini ; Labadie, Guillermo R ; O J Porta, Exequiel ; Ballari, María Sol

Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker. A combination of bioassay, cheminformatics, docking, and in silico ADME-Tox was also performed. SAR analysis that analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, three compounds display superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behavior of the collection on migration and invasion, a key process in tumor metastasis, was also studied. Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity.

100 Deals associated with Salirasib

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External Link

KEGG	Wiki	ATC	Drug Bank
D08995	-	-	DB12681

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Lung Non-Small Cell Carcinoma	Phase 2	US	Concordia Pharmaceuticals, Inc.	01 Sep 2007
Colorectal Cancer	Phase 2	US	Kadmon Pharmaceuticals LLC	-
Non-Small Cell Lung Cancer	Phase 2	-	Ono Pharmaceutical Co., Ltd.	-
Pancreatic Cancer	Phase 2	US	-	-
Pancreatic Cancer	Phase 2	-	Ono Pharmaceutical Co., Ltd.	-
Solid tumor	Phase 2	JP	Ono Pharmaceutical Co., Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2009	Phase 2	Non-small cell lung cancer stage IIIB	33	Salirasib	(semtrfefsb) = agsplrpydo tpdlcbxqlw (lobdwoafzt ) View more	-	20 May 2009
ASCO2007	Phase 1	Refractory Hematologic Malignancy	12	s-trans, trans-farnesylthiosalicylic acid (FTS)	tqniswkqoq(copsbjnhdk) = nofurzmklj hkktydkvcz (czqyyrzadi )	Positive	20 Jun 2007