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

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)

+ [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/Sequence

Molecular FormulaC26H30N6O3

InChIKeyXKFTZKGMDDZMJI-HSZRJFAPSA-N

CAS Registry827318-97-8

Aurora-A (AURKA) is serine/threonine protein kinase involved in the regulation of numerous processes of cell division. Numerous studies have demonstrated strong association between AURKA and cancer. AURKA is overexpressed in many cancers, such as colon, breast and prostate cancers. Consequently, AURKA has emerged as promising target for therapeutic intervention in cancer management. Herein, we describe a computational workflow for the discovery of novel anti-AURKA inhibitory leads starting with ligand-based assessment of the pharmacophoric space of six diverse sets of inhibitors. Subsequently, machine learning/QSAR modeling was coupled with genetic function algorithm to search for the best possible combination of machine learner, ligand-based pharmacophore(s) and molecular descriptors capable of explaining variation in anti-AURKA bioactivities within a collected list of inhibitors. Two learners succeeded in achieving acceptable structure/activity correlations, namely, random forests and extreme gradient boosting (XGBoost). Three pharmacophores emerged in the successful ML models. These were then used as 3D search queries to mine the National Cancer Institute database for novel anti-AURKA leads. Top-ranking 38 hits were assessed in vitro for their anti-AURKA bioactivities. Among them, three compounds exhibited promising dose-response curves, demonstrating experimental IC₅₀ values ranging from sub-micromolar to low micromolar values. Remarkably, two of these compounds are of novel chemotypes.

01 Nov 2024·Journal of Molecular Liquids

Identification of Aurora A kinase allosteric inhibitors: A comprehensive virtual screening through fingerprint-based similarity search, molecular docking, machine learning and molecular dynamics simulation

Author: Sardarsinh Suryawanshi, Vikramsinh ; Chunarkar Patil, Pritee ; Pravin Pawar, Surbhi ; Abdelghani, Heba Taha M. ; Sudhir Kolpe, Mahima ; Bhowmick, Shovonlal

The Aurora A kinase (AAK) protein controls spindle assembly and promotes cell divisions in various diseases including cancer.In the present study, allosteric inhibition of AAK protein through different advanced computational screening approaches is employed to target AAK's allosteric inhibition-modulation.Precisely, extensive computational techniques including allosteric binding sites recognition of AAK protein, fingerprint-based similarity search, multi-step mol. docking through AutoDock Vina and PLANTS, and a 100 ns mol. dynamics (MD) simulations studies were carried out followed by the calculation of binding free energy with MM-GBSA based approaches, has been employed for identification of potential allosteric inhibitors-modulators of AAK protein.The study outcome highlighted that all three identified small mol. chem. entities exhibit strong binding interaction affinity in both the docking analyses at the allosteric domain of AAK protein and also greater interaction stability in comparison to the considered standard compoundIn addition, all identified three screened hits also show acceptable pharmacokinetics and medicinal chem. properties, which certainly dictates their potentiality for becoming good drug-like compounds for inhibiting-modulating the activity of AAK protein binds with similar amino acids of the allosteric domain of AAK protein with selected three compoundsAll the selected mols. were found to show an acceptable ADMET profile.Moreover, the MM-GBSA-based binding energy was found to be in the range of -8 to -35 Kcal/mol, which showed a strong association between proposed mols. and AAK protein.Comprehensive computational approach shows that the selected proposed three inhibitors of AAK protein are the best candidates as potential inhibitors.

01 Aug 2024·Cancer Letters

Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids

Article

Author: Cheong, Io Hong ; Kozlakidis, Zisis ; Du, Yutong ; Yan, Ranlin ; Zang, Lu ; Li, Chen ; Zhu, Zhenggang ; Kwan, Wingyan ; Yang, Ruixin ; Yu, Yingyan

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.

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	Preclinical	Italy	Nerviano Medical Sciences Group SRL	26 Mar 2017
Small Cell Lung Cancer	Preclinical	Italy	Nerviano Medical Sciences Group SRL	26 Feb 2017
Multiple Myeloma	Preclinical	United States	Nerviano Medical Sciences S.r.l	01 Oct 2008
Multiple Myeloma	Preclinical	France	Nerviano Medical Sciences S.r.l	01 Oct 2008
Castration-Resistant Prostatic Cancer	Preclinical	Netherlands	Nerviano Medical Sciences Group SRL	07 Feb 2008
Metastatic castration-resistant prostate cancer	Preclinical	Italy	Nerviano Medical Sciences S.r.l	01 Sep 2007

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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	(bipjrvpbnl) = qduqkzdgca tftjtcoasp (gbsjogwbmq ) View more	-	20 May 2013
ASCO2011	Phase 2	Metastatic castration-resistant prostate cancer Second line	43	Danusertib 330 mg/m2 over 6h IV	(gesfarkzku) = gzfphbdckf lhaentdgnk (zhnagnsosw, 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	(gesfarkzku) = tbmzxjffsw lhaentdgnk (zhnagnsosw, 10.71 - 17.29)	-	20 May 2011
ASCO2008	Phase 1	HR-positive/HER2-low Solid Tumors	40	PHA-739358 without G-CSF	(nmlykggsqk) = resephaltz hvltpvrikj (smjkfiudat ) View more	-	20 May 2008