Delving into the Latest Updates on OSI-7904L with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [7]

Target

TYMS

Action

inhibitors

Mechanism

TYMS inhibitors(Thymidylate synthase inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersInfectious Diseases

Active Indication-

Inactive Indication

adenocarcinoma of biliary tractAdvanced Malignant Solid NeoplasmBiliary Tract Neoplasms+ [10]

Originator Organization

Gilead Sciences, Inc.

Active Organization-

Inactive Organization

OSI Pharmaceuticals, Inc.

OncoVista Innovative Therapies, Inc.OncoVista, Inc.

+ [1]

License Organization

Gilead Sciences, Inc.

OSI Pharmaceuticals, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC27H24N4O6

InChIKeyBRVFNEZMTRVUGW-QFIPXVFZSA-N

CAS Registry139987-54-5

During active proliferation phase of intra-erythrocytic cycle, the genome of P. falciparum is regulated epigenetically and evolutionary conserved parasite-specific histone proteins are extensively acetylated. The reversible process of lysine acetylation, causing transcriptional activation and its deacetylation, causing transcriptional repression is regulated by balanced activities of HATs and HDACs. They are also known to regulate antigenic variations and gametocytic conversion in P. falciparum. These histone modifying enzymes have been identified as potential targets for development of anitmalarials in literature. PfGCN5, a HAT family member of P. falciparum is predominantly involved in H3K9 acetylation. In this study, through comparative structure and sequence analysis, we elucidate differences in the catalytic pocket of PfGCN5 which can be exploited to design selective inhibitors. Through virtual screening of known antimalarials from ChEMBL bioassay database, we mapped 10 compounds with better affinity towards PfGCN5. Further, we identified 10 more novel compounds which showed remarkably better affinity towards the Plasmodium target from analogues of mapped inhibitors from ZINC database of commercially available compounds. Comparative molecular dynamics simulation study of one of the compounds (C14) complex with PfGCN5 and HsGCN5 suggested the possible reason for its selectivity. In vitro parasite growth assay in the presence of C14 showed IC50 value at lower nanomolar range (∼ 225 nM). However, no effect in mammalian fibroblast cells was observed for C14 (up to 20 μM). Further, reduced level of HAT activity of recombinant GCN5 and H3K9Ac was observed in the parasites treated with C14. Overall, this study reports 20 potential inhibitors of PfGCN5 and experimental validation of one molecule (C14) with antimalarial activity at low nanomolar range.

01 Jun 2011·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors

Q3 · MEDICINE

Article

Author: Roy L. Kisliuk ; Xilin Zhou ; Jennifer Piraino ; Aleem Gangjee ; Xin Zhang ; Vivian Cody

Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH₃ substituents inhibited human (h) TS (IC₅₀ =0.26-0.8 μM), but not hDHFR. Substitution of the 2-CH₃ with a 2-NH₂ increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC₅₀ = 0.09-0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.

01 Nov 2010·Mini-Reviews in Medicinal ChemistryQ3 · MEDICINE

Antifolate Inhibitors of Thymidylate Synthase as Anticancer Drugs

Q3 · MEDICINE

Review

Author: Jarmuła, A

Inhibitors of thymidylate synthase (TS) play an essential role in the pharmacological management of several tumors. Two antifolates, Raltitrexed and Pemetrexed, are licensed anticancer drugs, with Pemetrexed, unlike Raltitrexed, undergoing further intense clinical development. Other antifolate TS inhibitors, recently/currently tested in clinical studies, that show encouraging anticancer activities are Plevitrexed, GW7904L and Nolatrexed. A new prospect among antifolates, demonstrating a very desirable pattern of pharmacological properties, is BGC 945 that showed promising antitumor activities and has been nominated for clinical development. In this paper, apart from reviewing their biochemical and pharmacological properties, up-to-date characteristics of clinical development of all the mentioned agents are presented. In addition, trends and perspectives for developing improved antifolate inhibitors of TS and future drugs are discussed. Drug resistance is the main barrier to more effective treatment of cancers with antifolates; therefore, mechanisms of antifolate resistance and currently applied approaches to overcome it are also pointed out in the review.

100 Deals associated with OSI-7904L

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External Link

KEGG	Wiki	ATC	Drug Bank
-	OSI-7904L	-	DB05457

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
stomach adenocarcinoma	Phase 2	United States	OSI Pharmaceuticals, Inc.	01 Oct 2003
stomach adenocarcinoma	Phase 2	Belgium	OSI Pharmaceuticals, Inc.	01 Oct 2003
Biliary Tract Neoplasms	Phase 2	-	Gilead Sciences, Inc.	-
Biliary Tract Neoplasms	Phase 2	-	OncoVista Innovative Therapies, Inc.	-
Colorectal Cancer	Phase 2	-	OncoVista Innovative Therapies, Inc.	-
Colorectal Cancer	Phase 2	-	Gilead Sciences, Inc.	-
Esophageal Carcinoma	Phase 2	United States	OSI Pharmaceuticals, Inc.	-
Esophageal Carcinoma	Phase 2	Belgium	OSI Pharmaceuticals, Inc.	-
Esophageal Carcinoma	Phase 2	United Kingdom	OSI Pharmaceuticals, Inc.	-
Neoplasms	Phase 2	United States	OncoVista, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2009	Phase 2	Recurrent Squamous Cell Carcinoma of the Head and Neck	41	OSI-7904L	(hnfbsvwfsz) = ahedowtipu cmmuzvhzav (anrzcvewrq )	Negative	20 May 2009
ASCO2005	Phase 2	Neoplasms	53	OSI-7904L	(kinijfzkkj) = mvwdqklmiz gxyhqpxpod (cdptojvbsa, 6.2 - 28.3) View more	-	01 Jun 2005