Delving into the Latest Updates on Tosedostat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Tosedostat (USAN/INN)

Target-

Action

inhibitors

Mechanism

Aminopeptidase inhibitors

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Bladder Cancer

Inactive Indication

Acute Lymphoblastic LeukemiaAcute Myeloid LeukemiaAdvanced Malignant Solid Neoplasm+ [5]

Originator Organization

CTI BioPharma Corp.

Active Organization

Erasmus University Rotterdam

Inactive Organization

Chroma Therapeutics Ltd.

University of Cardiff

CTI BioPharma Corp.

License Organization

Ligand UK Research Ltd.

Chroma Therapeutics Ltd.

CTI BioPharma Corp.

Drug Highest PhasePreclinical

First Approval Date-

RegulationOrphan Drug (United States)

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Structure/Sequence

Molecular FormulaC21H30N2O6

InChIKeyFWFGIHPGRQZWIW-SQNIBIBYSA-N

CAS Registry238750-77-1

This phase I/II trial studies the side effects and best dose of cytarabine and azacitidine and how well they work when giving together with tosedostat in treating older participants with acute myeloid leukemia or high risk myelodysplastic syndrome. Tosedostat and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving tosedostat and cytarabine or azacitidine may work better in treating participants with acute myeloid leukemia or high risk myelodysplastic syndrome.

Start Date20 Nov 2012

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

[+1]

100 Clinical Results associated with Tosedostat

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100 Translational Medicine associated with Tosedostat

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100 Patents (Medical) associated with Tosedostat

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58

Literatures (Medical) associated with Tosedostat

01 Jul 2024·eBioMedicine

Advancing drug development for atrial fibrillation by prioritising findings from human genetic association studies

Article

Author: Finan, Chris ; Providencia, Rui ; Farmaki, Aliki-Eleni ; Kukendrarajah, Kishore ; Floriaan Schmidt, Amand ; Lambiase, Pier D ; Schilling, Richard

BACKGROUNDDrug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support from human genetics, by integrating the available evidence with bioinformatics sources relevant for AF drug development.METHODSGenetic hits for AF and related traits were identified through structured search of MEDLINE. Genes derived from each paper were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured searches and review of evidence on MEDLINE and ClinialTrials.gov for each drug and its association with AF.FINDINGS613 unique drugs were identified, with 21 already included in AF Guidelines. Cardiovascular drugs from classes not currently used for AF (e.g. ranolazine and carperitide) and anti-inflammatory drugs (e.g. dexamethasone and mehylprednisolone) had evidence of potential benefit. Further targets were considered druggable but remain open for drug development.INTERPRETATIONOur systematic approach, combining evidence from different bioinformatics platforms, identified drug repurposing opportunities and druggable targets for AF.FUNDINGKK is supported by Barts Charity grant G-002089 and is mentored on the AFGen 2023-24 Fellowship funded by the AFGen NIH/NHLBI grant R01HL092577. RP is supported by the UCL BHF Research Accelerator AA/18/6/34223 and NIHR grant NIHR129463. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989 and UCL BHF Accelerator AA/18/6/34223 as well as the UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1 and by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. AF is supported by UCL BHF Accelerator AA/18/6/34223. CF is supported by UCL BHF Accelerator AA/18/6/34223.

15 May 2024·Cancer Research

NPEPPS Is a Druggable Driver of Platinum Resistance

Article

Author: Mahmoudi, Tokameh ; Xander, Nathaniel ; Parker, Sarah J. ; Joshi, Molishree ; Araki, Stephanie P. ; Jean, Annie ; Goodspeed, Andrew ; Jones, Robert T. ; Vekony, Hedvig ; Kan, Tsung Wai ; Mohapatra, Saswat ; Laajala, Teemu D. ; Tilton, Charlene B. ; Deiter, Cailin ; Theodorescu, Dan ; Scholtes, Mathijs ; Akbarzadeh, Maryam ; Zuiverloon, Tahlita C.M. ; Feldman, Lily Elizabeth ; Romal, Shahla ; Orman, Michael V. ; Clambey, Eric T. ; Layer, Ryan ; Costello, James C. ; Javaid, Mahmood

AbstractThere is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, while NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations.Significance:Targeting NPEPPS, which induces cisplatin resistance by controlling intracellular drug concentrations, is a potential strategy to improve patient responses to platinum-based therapies and lower treatment-associated toxicities.

01 Apr 2024·Cell Reports

Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer

Article

Author: Kelliher, Michelle A ; Ali, Amjad ; Chowdhury, Shreya Roy ; Thakare, Ritesh P ; Green, Michael R ; Malonia, Sunil K ; Ye, Tianyi ; Zhu, Lihua Julie ; Hu, Kai ; Eisenhaber, Frank ; Kulshreshtha, Ankur ; Su, Chinh Tran-To ; Deibler, Sara K ; Banday, Shahid ; Eisenhaber, Birgit ; Simin, Karl ; Mishra, Alok K ; Pham, Ngoc N H ; Simone, Tessa M ; Thompson, Paul R

CD24 is frequently overexpressed in ovarian cancer and promotes immune evasion by interacting with its receptor Siglec10, present on tumor-associated macrophages, providing a "don't eat me" signal that prevents targeting and phagocytosis by macrophages. Factors promoting CD24 expression could represent novel immunotherapeutic targets for ovarian cancer. Here, using a genome-wide CRISPR knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment 1), a factor that catalyzes the attachment of a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins, as a positive regulator of CD24 cell surface expression. Genetic ablation of GPAA1 abolishes CD24 cell surface expression, enhances macrophage-mediated phagocytosis, and inhibits ovarian tumor growth in mice. GPAA1 shares structural similarities with aminopeptidases. Consequently, we show that bestatin, a clinically advanced aminopeptidase inhibitor, binds to GPAA1 and blocks GPI attachment, resulting in reduced CD24 cell surface expression, increased macrophage-mediated phagocytosis, and suppressed growth of ovarian tumors. Our study highlights the potential of targeting GPAA1 as an immunotherapeutic approach for CD24⁺ ovarian cancers.

100 Deals associated with Tosedostat

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External Link

KEGG	Wiki	ATC	Drug Bank
D10026	-	-	DB11781

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Phase 2	United Kingdom	University of Cardiff	-
Acute Lymphoblastic Leukemia	Phase 2	Denmark	University of Cardiff	-
Acute Myeloid Leukemia	Phase 2	United Kingdom	University of Cardiff	-
Acute Myeloid Leukemia	Phase 2	Denmark	CTI BioPharma Corp.	-
Myelodysplastic Syndromes	Phase 2	Denmark	University of Cardiff	-
Myelodysplastic Syndromes	Phase 2	United Kingdom	University of Cardiff	-
Acute Myeloid Leukemia	Discovery	Denmark	CTI BioPharma Corp.	-
Acute Myeloid Leukemia	Discovery	United Kingdom	University of Cardiff	-
Myelodysplastic Syndromes	Discovery	United Kingdom	University of Cardiff	-
Myelodysplastic Syndromes	Discovery	Denmark	University of Cardiff	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02352831 (CTgov)	Phase 1/2	Pancreatic adenocarcinoma metastatic	16	Fresh tissue biopsy+Tosedostat+Capecitabine (Phase I (Tosedostat + Capecitabine))	igqjmkncni(pmlvirijsw) = tcwytvrxhd nkhuzvkdzt (fvdbbesttw, ouaidaqwoy - utywunmvlm) View more	-	17 Dec 2018
NCT02352831 (CTgov)	Phase 1/2	Pancreatic adenocarcinoma metastatic	16	Fresh tissue biopsy+Tosedostat+Capecitabine (Phase II (Tosedostat + Capecitabine))	fdpfcjqqxq(gghjzllwku) = zhfkmvemyx qktebtttou (qpftdrktxy, znbiucjzaa - xoaulvmafh) View more	-	17 Dec 2018
ASH2018	Not Applicable	Gastrointestinal Neoplasms	535	Apixaban	(fyehckqnxv) = gureikneau uqmetptsfy (kewatcmsex ) View more	-	29 Nov 2018
ASH2018	Not Applicable	Gastrointestinal Neoplasms	535	Rivaroxaban	(fyehckqnxv) = zlnkosqtxi uqmetptsfy (kewatcmsex ) View more	-	29 Nov 2018
NCT02452346 (IST-CTI-MDS, CTgov)	Phase 2	Myelodysplastic Syndromes	12	Tosedostat	(imtwtmzguj) = nmpgdvtmfx vraraktlet (lbpaeulekh, jtsxikckqv - ayxyfpygma) View more	-	12 Jun 2018
NCT02452346 (ASH 12017 \| ASH 22017) Manual	Phase 2	Myelodysplastic Syndromes	12	azacitidine+Tosedostat	(skufbrlgks) = dlgalkvsae nfhfiboshl (phsfdfimlh ) View more	Positive	07 Dec 2017
NCT02352831 (ASCO_GI 12017 \| ASCO_GI 22017) Manual	Phase 1/2	Metastatic Pancreatic Ductal Adenocarcinoma First line	-	capecitabine+tosedostat	(gjkdnoqrcc) = none ghbfnmolip (tprbdgxntf )	Positive	20 Jan 2017
NCT02352831 (ASCO_GI2016)	Phase 1/2	Pancreatic adenocarcinoma metastatic	36	Tosedostat 120mg + Capecitabine 1000mg/m2	(pstgktyrlm) = vaiytbvesd lvwdzgoopv (hicjtaljhl )	-	01 Feb 2016
NCT02352831 (ASCO_GI2016)	Phase 1/2	Pancreatic adenocarcinoma metastatic	36	Tosedostat 60mg + Capecitabine 1000mg/m2	(pstgktyrlm) = qxdpsxcrhk lvwdzgoopv (hicjtaljhl )	-	01 Feb 2016
EUCTR2012-000334-19-IT (EHA2015)	Phase 2	Acute Myeloid Leukemia	33	Tosedostat 120 milligrams	(kjhvmpnlcn) = ddilcvzwgi ghpgntifwa (bphpppyuhu ) View more	-	21 May 2015
Pubmed \| J Clin Oncol	Phase 1/2	Acute Myeloid Leukemia \| Myelodysplastic Syndromes	-	Tosedostat	(dslpzcsbwr) = dwlxehpali fosfcblsiw (fsjckwtfut ) View more	Positive	01 Oct 2010
NCT00780598 (OPAL, ASCO2010)	Phase 2	Acute Myeloid Leukemia	-	Tosedostat 120 mg	(citivewgox) = 31.4% hsisvwenla (eazlvlmjho )	-	20 May 2010
NCT00780598 (OPAL, ASCO2010)	Phase 2	Acute Myeloid Leukemia	-	Tosedostat 240 mg	(citivewgox) = 31.4% hsisvwenla (eazlvlmjho )	-	20 May 2010
ASCO2007	Phase 1	HR-positive/HER2-low Solid Tumors	37	CHR-2797	(gfqnmjemkf) = pdbtfshgvb ldzqjkvgsc (sndlfdydze ) View more	-	20 Jun 2007