Delving into the Latest Updates on Tozasertib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Tozasertib (USAN), Tozasertib Lactate

+ [1]

Target

Aurora A x Aurora B x Aurora C x Bcr-Abl T315I x FLT3

Action

inhibitors

Mechanism

Aurora A inhibitors(Serine/threonine-protein kinase Aurora-A inhibitors), Aurora B inhibitors(Serine/threonine-protein kinase Aurora-B inhibitors), Aurora C inhibitors(Serine/threonine-protein kinase Aurora-C inhibitors)

+ [2]

Therapeutic Areas

NeoplasmsImmune System DiseasesDigestive System Disorders+ [3]

Active Indication-

Inactive Indication

Acute Lymphoblastic LeukemiaAdvanced cancerB-Cell Prolymphocytic Leukemia+ [9]

Originator Organization

Vertex Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Merck GmbH

Merck & Co., Inc.

Merck Sharp & Dohme Corp.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC23H28N8OS

InChIKeyGCIKSSRWRFVXBI-UHFFFAOYSA-N

CAS Registry639089-54-6

INTRODUCTIONSenescence refers to a state of permanent cell growth arrest and is regarded as a tumor suppressive mechanism, whereas accumulative evidence demonstrate that senescent cells play an adverse role during cancer progression. The scarcity of specific and reliable markers reflecting senescence level in cancer impede our understanding of this biological basis.OBJECTIVESSenescence-related genes (SRGs) were collected for integrative analysis to reveal the role of senescence in hepatocellular carcinoma (HCC).METHODSConsensus clustering was used to subtype HCC based on SRGs. Several computational methods, including single sample gene set enrichment analysis (ssGSEA), fuzzy c-means algorithm, were performed. Data of drug sensitivities were utilized to screen potential therapeutic agents for different senescence patients. Additionally, we developed a method called signature-related gene analysis (SRGA) for identification of markers relevant to phenotype of interest. Experimental strategies consisting quantitative real-time PCR (qRT-PCR), β-galactosidase assay, western blot, and tumor-T cell co-culture system were used to validate the findings in vitro.RESULTSWe identified three robust prognostic clusters of HCC patients with distinct survival outcome, mutational landscape, and immune features. We further extracted signature genes of senescence clusters to construct the senescence scoring system and profile senescence level in HCC at bulk and single-cell resolution. Senescence-induced stemness reprogramming was confirmed both in silico and in vitro. HCC patients with high senescence were immune suppressed and sensitive to Tozasertib and other drugs. We suggested that MAFG, PLIN3, and 4 other genes were pertinent to HCC senescence, and MAFG potentially mediated immune suppression, senescence, and stemness.CONCLUSIONOur findings provide insights into the role of SRGs in patients stratification and precision medicine.

01 Jan 2025·Archiv der Pharmazie

Design and synthesis of pyridazin‐4‐one derivatives as necroptosis inhibitors

Article

Author: Zhou, Xuan ; Feng, Dazhi ; Fang, Chen ; Duan, Wenhu ; Peng, Xia ; Zhang, Hefeng ; Liu, Kaiyuan ; Geng, Meiyu ; Wang, Tianchen ; An, Yuxiang ; Ai, Jing

AbstractNecroptosis is a regulated inflammatory cell death process that is closely associated with autoimmune diseases, acute ischemic injuries, neurodegenerative disorders, and so on. Due to the crucial role of receptor‐interacting protein kinase 1 (RIPK1) in the necroptosis pathway, RIPK1 inhibitors are believed to have great potential in the treatment of necroptosis‐related diseases. In this article, we reported a series of pyridazin‐4‐one derivatives as potent necroptosis inhibitors for both human and mouse cells. The representative compound 13 exhibited favorable RIPK1 selectivity and dose‐dependently inhibited RIPK1 phosphorylation. The in vivo pharmacokinetic study indicated that compound 13 was an orally available candidate. Finally, molecular docking and molecular dynamics simulations were performed to elucidate the binding pattern of compound 13 with RIPK1. Collectively, compound 13 represents a promising lead compound for the future development of RIPK1‐targeted necroptosis inhibitors.

31 Dec 2024·Annals of Medicine

Establishment and validation of the prognostic risk model based on the anoikis-related genes in esophageal squamous cell carcinoma

Article

Author: Cao, Shasha ; Niu, Wei ; Duan, Lijuan ; Cui, Zhiying ; Li, Ming ; Gao, Zhaowei ; Li, Yutong ; Zhang, Yaowen ; Li, Junkuo ; Zhu, Weiwei ; Lun, Shumin

BACKGROUNDEsophageal squamous cell carcinoma (ESCC) is a malignant condition in humans. Anoikis-related genes (ARGs) are crucial to cancer progression. Therefore, more studies on the relationship between ARGs and ESCC are warranted.METHODSThe study acquired ESCC-related transcriptome data from TCGA. Differentially expressed ARGs (DE-ARGs) were obtained by differential analysis and candidates were filtered out by survival analysis. Prognostic genes were determined by Cox and LASSO regression. A risk model was constructed based on prognostic gene expressions. An immune infiltration study was done to explain how these genes contribute to ESCC development. The IC50 test was adopted to assess the clinical response of chemotherapy drugs. Single cell analysis was performed on the GSE145370 dataset. Moreover, the prognostic gene expressions were detected by qRT-PCR.RESULTS53 DE-ARGs were screened and four candidate genes including PBK, LAMC2, TNFSF10 and KL were obtained. Cox and LASSO regression identified the two prognostic genes, TNFSF10 and PBK. Immuno-infiltration analysis revealed positive associations of PBK with Macrophages M0 cells, and TNFSF10 with Macrophages M1 cells. The IC50 values of predicted drugs, in the case of Tozasertib 1096 and WIKI4 1940, were significantly variant between risk groups. Single cell analysis revealed that TNFSF10 and PBK levels were higher in epithelial cells than in other cells. The prognostic genes expression results by qRT-PCR were compatible with the dataset analysis.CONCLUSIONThe study established an ARG prognosis model of ESCC. It provided a reference for the research of ARGs in ESCC.

100 Deals associated with Tozasertib

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External Link

KEGG	Wiki	ATC	Drug Bank
D08279	Tozasertib	-	-

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 2	United States	Merck GmbH	-
Hematologic Neoplasms	Phase 2	United States	Merck GmbH	-
Hematologic Neoplasms	Phase 2	Singapore	Merck GmbH	-
Hematologic Neoplasms	Phase 2	Colombia	Merck GmbH	-
Hematologic Neoplasms	Phase 2	European Union	Merck GmbH	-
Hematologic Neoplasms	Phase 2	Russia	Merck GmbH	-
Hematologic Neoplasms	Phase 2	Japan	Merck GmbH	-
Hematologic Neoplasms	Phase 2	South Korea	Merck GmbH	-
Hematologic Neoplasms	Phase 2	Israel	Merck GmbH	-
Non-Small Cell Lung Cancer	Phase 2	United States	Merck GmbH	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00111683 (Pubmed \| Leukemia)	Phase 1/2	-	77	MK-0457	(cafguyhdje) = ltkbmzotzk swgjigmbez (zhagycmbcp ) View more	-	01 Jan 2013
Pubmed \| Cancer Chemother Pharmacol	Phase 1	Advanced Malignant Solid Neoplasm	-	MK-0457	(jkaqsgvgol) = fudpjlxzhv yhxjdmzize (llegoijhbw ) View more	-	01 Feb 2011
ASCO2006	Phase 1	Neoplasms	16	MK-0457	(kabuklujgt) = nyhfgmyksf zxcohtjacd (prafppaicx, ± 141) View more	-	20 Jun 2006