Delving into the Latest Updates on Nolatrexed Dihydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Nolatrexed, Orataq, Thymitaq

+ [4]

Target

TYMS

Action

inhibitors

Mechanism

TYMS inhibitors(Thymidylate synthase inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersMouth and Tooth Diseases+ [4]

Active Indication-

Inactive Indication

Colorectal CancerHead and Neck NeoplasmsHepatocellular Carcinoma+ [8]

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Agouron Pharmaceuticals LLC

Beijing Konruns Pharmaceutical Co., Ltd.

Eximias Pharmaceutical Corp.

Drug Highest PhaseDiscontinuedNDA/BLA

First Approval Date-

RegulationOrphan Drug (United States)

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Structure/Sequence

Molecular FormulaC14H12N4OS

InChIKeyXHWRWCSCBDLOLM-UHFFFAOYSA-N

CAS Registry147149-76-6

View All Structures (2)

Primary objective: To evaluate the objective response rate (ORR) of nolatrexed hydrochloride in the treatment of locally advanced or metastatic head and neck squamous cell carcinoma that has failed previous platinum-containing regimens. Secondary objectives: (1) To evaluate the disease control rate (DCR) and progression-free survival (PFS); (2) To evaluate the safety and tolerability of nolatrexed hydrochloride for injection.

Start Date-

Sponsor / Collaborator

Beijing Konruns Pharmaceutical Co., Ltd.

NCT00012324

/ CompletedPhase 3

A Phase III Randomized Controlled Study Comparing the Survival of Patients With Unresectable Hepatocellular Carcinoma (HCC) Treated With THYMITAQ to Patients Treated With Doxorubicin

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which chemotherapy regimen is more effective for liver cancer.
PURPOSE: Randomized phase III trial to compare the effectiveness of two different chemotherapy regimens in treating patients who have recurrent or unresectable liver cancer.

Start Date01 Sep 2000

Sponsor / Collaborator

Eximias Pharmaceutical Corp.

100 Clinical Results associated with Nolatrexed Dihydrochloride

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100 Translational Medicine associated with Nolatrexed Dihydrochloride

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100 Patents (Medical) associated with Nolatrexed Dihydrochloride

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182

Literatures (Medical) associated with Nolatrexed Dihydrochloride

09 Aug 2024·ACS Infectious Diseases

Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-Trypanosoma brucei Agents

Article

Author: Tavares, Joana ; Tagliazucchi, Lorenzo ; Konchie Simo, Claude U ; Landi, Giacomo ; Rizzo, Marco ; Tonelli, Michele ; Schenone, Silvia ; Cordeiro-da-Silva, Anabela ; Saporito, Giulia ; Santarém, Nuno ; Costi, Maria Paola ; Carbone, Anna ; Pozzi, Cecilia ; Mangani, Stefano ; Francesconi, Valeria

Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles (1) and 2-guanidino benzimidazoles (2), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS). The crystal structures of TbDHFR and TbPTR1 in complex with selected compounds experienced in both cases a substrate-like binding mode and allowed the rationalization of the main chemical features supporting the inhibitor ability to target folate enzymes. Biological evaluation of both series was performed against T. brucei and L. infantum and the toxicity against THP-1 human macrophages. Notably, the 5,6-dimethyl-2-guanidinobenzimidazole 2g resulted to be the most potent (K_i = 9 nM) and highly selective TbDHFR inhibitor, 6000-fold over TbPTR1 and 394-fold over hDHFR. The 5,6-dimethyl tricyclic analogue 1g, despite showing a lower potency and selectivity profile than 2g, shared a comparable antiparasitic activity against T. brucei in the low micromolar domain. The dichloro-substituted 2-guanidino benzimidazoles 2c and 2d revealed their potent and broad-spectrum antitrypanosomatid activity affecting the growth of T. brucei and L. infantum parasites. Therefore, both chemotypes could represent promising templates that could be valorized for further drug development.

01 May 2024·Toxicology and Applied Pharmacology

In silico and in vitro assessment of drugs potentially causing adverse effects by inhibiting CYP17A1

Article

Author: Naeem, Sadaf ; Odermatt, Alex ; Jäger, Marie-Christin ; Smieško, Martin ; Kędzierski, Jacek

Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP enzymes are frequently investigated as anti-targets, the inhibition of CYP enzymes involved in adrenal steroidogenesis is not well studied. The steroidogenic enzyme CYP17A1 is a dual-function enzyme catalyzing hydroxylase and lyase reactions relevant for the biosynthesis of adrenal glucocorticoids and androgens. Inhibition of CYP17A1-hydroxylase leads to pseudohyperaldosteronism with subsequent excessive mineralocorticoid receptor activation, hypertension and hypokalemia. In contrast, specific inhibition of the lyase function might be beneficial for the treatment of prostate cancer by decreasing adrenal androgen levels. This study combined in silico and in vitro methods to identify drugs inhibiting CYP17A1. The most potent CYP17A1 inhibitors identified are serdemetan, mocetinostat, nolatrexed, liarozole, and talarozole. While some of these drugs are currently under investigation for the treatment of various cancers, their potential for the treatment of prostate cancer is yet to be explored. The DrugBank database was screened for CYP17A1 inhibitors, to increase the awareness for the risk of drug-induced pseudohyperaldosteronism and to highlight drugs so far unknown for their potential to cause side effects resulting from CYP17A1 inhibition.

01 Feb 2024·Journal of Mathematical Chemistry

Identification of potential oral cancer drugs as Bcl-2 inhibitors from known anti-neoplastic agents through docking studies

Author: Pal, Debnath ; Raychaudhury, Chandan ; Srinivasan, Shreyaa

Oral Cancer is one of the major killers in India and of global concern.An attempt has been made here to identify small mol. inhibitors of Bcl-2 (B-cell lymphoma 2) protein through docking studies in search of new oral cancer drugs from a curated set of 276 known anti-neoplastic agents obtained from PubChem.The Bcl-2 protein (PDB id:6QGH), being complexed with ligand ABT-263, has been detached from the complex.The ligand-free protein and 276 compounds have been prepared for docking studies using corresponding tools available in Discovery Studio (DS), ver.4.1.The 276 compounds have been docked on the first site of the protein using LibDock docking program available in DS.By considering Methotrexate as the reference compound (LibDock score: 114.76), we have identified 25 compounds as the most potential oral cancer drugs having LibDock scores greater than 100.Another set of 114 compounds with LibDock scores between 80 and 100 have also been identified as the next set of potential drug candidates and some of them show anti-apoptosis properties.Two other compounds with LibDock scores below 80 have been identified for comparative analyses with some high-scoring compoundsThe docking results have been given in tables and pictures (screenshots) of the docked poses of selected compounds have been shown to illustrate the findings.Finally, the most suitable potential compounds have been identified by applying Lipinski′s Rule of 5.The present approach using known anti-neoplastic agents is believed to help discover potential anti-oral cancer drug candidates.

100 Deals associated with Nolatrexed Dihydrochloride

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Nolatrexed Dihydrochloride	-	DB12912

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	NDA/BLA	China	Beijing Konruns Pharmaceutical Co., Ltd.	19 Jan 2015
Nasopharyngeal Neoplasms	NDA/BLA	China	Beijing Konruns Pharmaceutical Co., Ltd.	19 Jan 2015
Unresectable Hepatocellular Carcinoma	NDA/BLA	United States	Eximias Pharmaceutical Corp.	01 Sep 2000
Unresectable Hepatocellular Carcinoma	NDA/BLA	Canada	Eximias Pharmaceutical Corp.	01 Sep 2000
Unresectable Hepatocellular Carcinoma	NDA/BLA	Puerto Rico	Eximias Pharmaceutical Corp.	01 Sep 2000
Colorectal Cancer	NDA/BLA	United States	Agouron Pharmaceuticals LLC	-
Liver Cancer	NDA/BLA	South Africa	Agouron Pharmaceuticals LLC	-
Liver Cancer	NDA/BLA	Europe	Agouron Pharmaceuticals LLC	-
Pancreatic Cancer	NDA/BLA	United States	Agouron Pharmaceuticals LLC	-
Prostatic Cancer	NDA/BLA	United States	Agouron Pharmaceuticals LLC	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Pubmed \| J Clin Oncol	Phase 3	Unresectable Hepatocellular Carcinoma	445	Nolatrexed	(ixbjbvkstb) = nvhfmxoqrl rqslcglkrj (tujsqbmtus ) View more	Negative	20 Jul 2007
				Doxorubicin	(ixbjbvkstb) = vgzasgnphj rqslcglkrj (tujsqbmtus ) View more
ASCO2005	Phase 1	Advanced cancer	8	Nolatrexed dihydrochloride	cktwzyycna(axhsxowqiw) = vjytnpmfki zwonpftria (svfueehzkm, 2.86 - 6.19)	-	01 Jun 2005
ETHECC (ASCO2005)	Phase 3	Hepatocellular Carcinoma	446	Nolatrexed dihydrochloride (THYMITAQ)	hcrzywpgas(yjsbcmgvqb) = vpgaeuhbaq rkhhxekhgm (pnkloowdgz ) View more	-	01 Jun 2005
				Doxorubicin (Adriamycin)	dxpzlzaech(wucwpkbhbp) = cwvbaqcxyw wnrcfpssfm (icmvkzinac )
ASCO2004	Phase 2	Metastatic hepatocellular carcinoma	54	Nolatrexed dihydrochloride	xapqkyqpof(uazxchqkim) = kqrnowkfzm gonhbktqft (uynqpkncko )	-	15 Jul 2004
				Doxorubicin	xapqkyqpof(uazxchqkim) = yunauxdhyd gonhbktqft (uynqpkncko )