Delving into the Latest Updates on Danusertib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

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

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)

+ [1]

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Philadelphia chromosome positive chronic myelogenous leukemia

Inactive Indication

Castration-Resistant Prostatic CancerMetastatic castration-resistant prostate cancerMultiple Myeloma+ [2]

Originator Organization

Nerviano Medical Sciences S.r.l

Active Organization

Nerviano Medical Sciences S.r.l

Inactive Organization

Nerviano Medical Sciences Group SRL

National Cancer Institute

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC26H30N6O3

InChIKeyXKFTZKGMDDZMJI-HSZRJFAPSA-N

CAS Registry827318-97-8

Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with aggressiveness and poor prognosis. It is of great significance to find sensitive drugs for DGC. In the current study, a total of 20 patient-derived organoids (PDOs) were analyzed for screening the therapeutic efficacy of small molecule kinases inhibitors on gastric cancers, especially the therapeutic difference between intestinal-type gastric cancer (IGCs) and DGCs. The IGCs are sensitive to multiple kinases inhibitors, while DGCs are resistant to most of these kinases inhibitors. It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors (AURKi) Barasertib-HQPA and Danusertib. The cell diameter of cancer cells are increased with stronger staining of senescence-associated β-galactosidase (SA-β-GAL), and characteristic appearance of multinucleated giant cells. The senescent cancer cells secrete large amounts of chemokine MCP-1/CCL2, which recruit and induce macrophage to M2-type polarization in PDOs of DGC (DPDOs)-macrophage co-culture system. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2) expressed on macrophages and suppress their innate immunity to cancer cells. Overall, the special response of DGC to AURKi suggests that clinicians should select a sequential therapy with senescent cell clearance after AURKi treatment for DGC.

24 Jun 2024·Journal of Chemical Information and Modeling

Understanding the Differences of Danusertib’s Residence Time in Aurora Kinases A/B: Dissociation Paths and Key Residues Identified using Conventional and Enhanced Molecular Dynamics Simulations

Article

Author: Alzate-Morales, Jans ; Bravo-Moraga, Felipe ; Bedoya, Mauricio ; Vergara-Jaque, Ariela

The accurate experimental estimation of protein-ligand systems' residence time (τ) has become very relevant in drug design projects due to its importance in the last stages of refinement of the drug's pharmacodynamics and pharmacokinetics. It is now well-known that it is not sufficient to estimate the affinity of a protein-drug complex in the thermodynamic equilibrium process in in vitro experiments (closed systems), where the concentrations of the drug and protein remain constant. On the contrary, it is mandatory to consider the conformational dynamics of the system in terms of the binding and unbinding processes between protein and drugs in in vivo experiments (open systems), where their concentrations are in constant flux. This last model has been proven to dictate much of several drugs' pharmacological activities in vivo. At the atomistic level, molecular dynamics simulations can explain why some drugs are more effective than others or unveil the molecular aspects that make some drugs work better in one molecular target. Here, the protein kinases Aurora A/B, complexed with its inhibitor Danusertib, were studied using conventional and enhanced molecular dynamics (MD) simulations to estimate the dissociation paths and, therefore, the computational τ values and their comparison with experimental ones. Using classical molecular dynamics (cMD), three differential residues within the Aurora A/B active site, which seems to play an essential role in the observed experimental Danusertib's residence time against these kinases, were characterized. Then, using WT-MetaD, the relative Danusertib's residence times against Aurora A/B kinases were measured in a nanosecond time scale and were compared to those τ values observed experimentally. In addition, the potential dissociation paths of Danusertib in Aurora A and B were characterized, and differences that might be explained by the differential residues in the enzyme's active sites were found. In perspective, it is expected that this computational protocol can be applied to other protein-ligand complexes to understand, at the molecular level, the differences in residence times and amino acids that may contribute to it.

01 May 2024·Biochemical Pharmacology

Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor

Article

Author: Zhu, Wentao ; Xu, Yi ; He, Jiahuang ; Lei, Ying ; Jin, Xuru ; Liu, Zitian ; Zhang, Xiang ; Chen, Xiang

Aurora kinase (AURK) and heat shock factor 1 (HSF1) are commonly overexpressed in non-small cell lung cancer (NSCLC), correlating with poor prognosis. This study aims to assess the therapeutic potential of combining the Danusertib (Danu, AURK inhibitor) and KRIBB11 (HSF1 inhibitor) for NSCLC treatment. The effects of this combination were investigated in A549 cells and a tumor xenograft mouse model. The findings demonstrate that concurrent administration of Danu and KRIBB11 effectively impedes cell proliferation, induces apoptosis, and triggers G2/M cell cycle arrest. Moreover, the combination treatment upregulates pro-apoptotic proteins (Cleaved-caspase3, Cleaved-PARP, and Bax) while downregulating anti-apoptotic proteins (Bcl-2), as well as G2/M-related proteins (CDC2 and cyclin B1). Additionally, the combination treatment elevates reactive oxygen species (ROS) levels, decreases mitochondrial membrane potential, and activates the DNA damage pathway. Interestingly, we discovered that the PI3K/AKT pathway is involved in mediating the effects of both Danu and KRIBB11. Furthermore, the combination treatment inhibits tumor growth and AKT signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/AKT signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways.

100 Deals associated with Danusertib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11778

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 2	-	Nerviano Medical Sciences S.r.l	-
Neuroblastoma	Phase 1	IT	Nerviano Medical Sciences Group SRL	26 Mar 2017
Small Cell Lung Cancer	Phase 1	IT	Nerviano Medical Sciences Group SRL	26 Feb 2017
Castration-Resistant Prostatic Cancer	Phase 1	NL	Nerviano Medical Sciences Group SRL	07 Feb 2008
Metastatic castration-resistant prostate cancer	Phase 1	IT	Nerviano Medical Sciences S.r.l	01 Sep 2007
Multiple Myeloma	Preclinical	US	Nerviano Medical Sciences S.r.l	01 Oct 2008
Multiple Myeloma	Preclinical	FR	Nerviano Medical Sciences S.r.l	01 Oct 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


EUCTR2006-003772-35-BE (not available, ASCO2013)	Phase 2	metastatic non-small cell lung cancer	56	Danusertib	(fabcwmhxbo) = tyupaxfqoj dzjcubihah (mxeaparrie ) View more	-	20 May 2013
ASCO2011	Phase 2	Metastatic castration-resistant prostate cancer Second line	43	Danusertib 330 mg/m2 over 6h IV	(fiwigbceln) = atefbwjfgf kpoprgugvh (gronyyyjwa, 10.86 - 15.14)	-	20 May 2011
ASCO2011	Phase 2	Metastatic castration-resistant prostate cancer Second line	43	Danusertib 500 mg/m2 over 24h IV	(fiwigbceln) = zfgmkzzjmm kpoprgugvh (gronyyyjwa, 10.71 - 17.29)	-	20 May 2011
ASCO2008	Phase 1	HR-positive/HER2-low Solid Tumors	40	PHA-739358 without G-CSF	(qoqunuamfo) = vfhfsabjhm jigdvkdvub (jrlqngiooq ) View more	-	20 May 2008