Delving into the Latest Updates on Imidacrine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Imidazoloacridine, Symadex, Symadex Pathfinder

+ [6]

Target

FLT3 x Top I x Top II

Action

inhibitors

Mechanism

FLT3 inhibitors(Tyrosine-protein kinase receptor FLT3 inhibitors), TOP1 inhibitors(DNA topoisomerase I inhibitors), Top II inhibitors(Topoisomerase II inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersSkin and Musculoskeletal Diseases+ [4]

Active Indication-

Inactive Indication

Acute Myeloid LeukemiaBreast CancerColitis, Ulcerative+ [5]

Originator Organization

University of Bradford

Active Organization-

Inactive Organization

Antisoma, Inc.

Sarossa Capital Ltd.

BTG International Ltd.

+ [1]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar concentrations of hydrophobic weak-base anticancer drugs. However, since lysosomal stress mediated by accumulation of weak-base drugs at such concentrations has never been proven and these drugs have diverse effects on malignant cells, we investigated whether the interpretation of the data was true. We found that lysosomal accumulation of the drugs daunorubicin, doxorubicin, mitoxantrone, symadex, chloroquine, clomipramine and sunitinib alone, was insufficient to induce lysosomal alkalization i.e., lysosomal stress-mediated biogenesis at nanomolar concentrations. Instead, we found that some of the drugs used induced G2 phase arrest and lysosomal biogenesis that is associated with activation of transcription factor EB (TFEB). Similarly, cantharidin, a control compound that does not belong to the weak base drugs, induced cell cycle arrest in the G2 phase associated with TFEB-driven lysosomal biogenesis. Overall none of the tested drugs caused stress-induced lysosomal biogenesis at nanomolar concentrations. However, daunorubicin, doxorubicin, mitoxantrone, symadex and cantharidin induced a massive block in the G2 phase of the cell cycle which is naturally associated with TFEB-driven lysosomal biogenesis.

01 May 2022·Bioorganic ChemistryQ2 · CHEMISTRY

Design, synthesis, and biological evaluation of novel pyrido-dipyrimidines as dual topoisomerase II/FLT3 inhibitors in leukemia cells

Q2 · CHEMISTRY

Article

Author: Nayl, A A ; Abdelhameid, Mohammed K ; Karam Farag, Ahmed ; Omar, Hany A ; Kandeel, Manal M ; Musa, Arafa ; Elmowafy, Mohammed ; Bukhari, Syed N A ; Shaker, Mohamed E ; Mohamed, Fatma E A ; Al-Sanea, Mohammad M ; Abdelgawad, Mohamed A ; Lamie, Phoebe F ; Ali, Sameeha M

Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of apoptosis, and late-stage apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several apoptosis biomarkers such as p53, TNFα, caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against topo II and FLT3 enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both enzymes.

01 May 2019·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

Electrochemical simulation of metabolism for antitumor-active imidazoacridinone C-1311 and in silico prediction of drug metabolic reactions

Q3 · MEDICINE

Article

Author: Żelaszczyk, Dorota ; Potęga, Agnieszka ; Mazerska, Zofia

The metabolism of antitumor-active 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) has been investigated widely over the last decade but some aspects of molecular mechanisms of its metabolic transformation are still not explained. In the current work, we have reported a direct and rapid analytical tool for better prediction of C-1311 metabolism which is based on electrochemistry (EC) coupled on-line with electrospray ionization mass spectrometry (ESI-MS). Simulation of the oxidative phase I metabolism of the compound was achieved in a simple electrochemical thin-layer cell consisting of three electrodes (ROXY^™, Antec Leyden, the Netherlands). We demonstrated that the formation of the products of N-dealkylation reactions can be easily simulated using purely instrumental approach. Newly reported products of oxidative transformations like hydroxylated or oxygenated derivatives become accessible. Structures of the electrochemically generated metabolites were elucidated on the basis of accurate mass ion data and tandem mass spectrometry experiments. In silico prediction of main sites of C-1311 metabolism was performed using MetaSite software. The compound was evaluated for cytochrome P450 1A2-, 3A4-, and 2D6-mediated reactions. The results obtained by EC were also compared and correlated with those of reported earlier for conventional in vitro enzymatic studies in the presence of liver microsomes and in the model peroxidase system. The in vitro experimental approach and the in silico metabolism findings showed a quite good agreement with the data from EC/ESI-MS analysis. Thus, we conclude here that the electrochemical technique provides the promising platform for the simple evaluation of drug metabolism and the reaction mechanism studies, giving first clues to the metabolic transformation of pharmaceuticals in the human body.

1

News (Medical) associated with Imidacrine

11 Dec 2007

·www.biospace.com

Xanthus Pharmaceuticals, Inc.'s Symadex Demonstrates Ability to Increase Spinal Cord Remyelination in Multiple Sclerosis Model

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Xanthus Pharmaceuticals, Inc. today presented preclinical data further supporting the potential for Symadex™ to reverse the clinical and pathological signs of multiple sclerosis (MS), including new data demonstrating increased spinal cord remyelination. The study was presented by Dr. Stephen J. Karlik, Ph.D., Professor of Diagnostic Radiology at the University of Western Ontario, London, Ontario and researchers from Xanthus at a meeting of the Multiple Sclerosis Society of Canada in Banff, Canada.

100 Deals associated with Imidacrine

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Phase 2	United States	Sarossa Capital Ltd.	-
Breast Cancer	Phase 2	-	Antisoma, Inc.	-
Breast Cancer	Phase 2	Europe	Sarossa Capital Ltd.	-
Breast Cancer	Phase 2	-	University of Bradford	-
Breast Cancer	Phase 2	-	BTG International Ltd.	-
Colorectal Cancer	Phase 2	-	Antisoma, Inc.	-
Colorectal Cancer	Phase 2	United Kingdom	Sarossa Capital Ltd.	-
Colorectal Cancer	Phase 2	-	BTG International Ltd.	-
Colorectal Cancer	Phase 2	-	University of Bradford	-
Multiple Sclerosis	Phase 2	United States	Sarossa Capital Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2008	Phase 2	Advanced breast cancer	53	C1311	zlpojjhnnk(swlpozuyki) = exjeurtlwv rjbzbvbdxg (igjqqskzvo ) View more	-	20 May 2008
C-1311 (ASCO2008)	Phase 1	HR-positive/HER2-low Solid Tumors	36	C-1311	(oikmmduysv) = kvvaydjimf fsqgryphns (slqgmcptxc ) View more	-	20 May 2008
ASCO2006	Phase 1	HR-positive/HER2-low Solid Tumors	16	C-1311	(upgvsccrua) = Grade 1 or 2 AEs most commonly reported as drug-related were nausea, asthenia, vomiting and diarrhea. fokxoiormi (ttujxaqwun ) View more	-	20 Jun 2006