Delving into the Latest Updates on L-Alanosine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Alanosine

+ [2]

Target

ADSS2

Mechanism

ADSS2 inhibitors(Adenylosuccinate synthetase 2 inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesDigestive System Disorders+ [5]

Active Indication-

Inactive Indication

Brain CancerCentral Nervous System NeoplasmsMesothelioma+ [8]

Originator Organization

University of California

Active Organization-

Inactive Organization

National Cancer Institute

Salmedix, Inc.

Teva Pharmaceutical Industries Ltd.

+ [1]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC3H7N3O4

InChIKeyMLFKVJCWGUZWNV-REOHCLBHSA-N

CAS Registry5854-93-3

RATIONALE: Drugs used in chemotherapy, such as alanosine, use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: This phase I trial is studying the side effects and best dose of alanosine in treating patients with high-grade progressive or recurrent malignant gliomas.

Start Date01 Mar 2004

Sponsor / Collaborator

National Cancer Institute

NCT00062283

/ CompletedPhase 2IIT

A Phase II, Open-Label, Non-Randomized, Multicenter, Single Agent Study of Intravenous SDX-102 for the Treatment of Patients With MTAP-Deficient Cancer

RATIONALE: Drugs used in chemotherapy such as alanosine use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: This phase II trial is studying how well alanosine works in treating patients with soft tissue sarcoma, sarcoma of the bone, mesothelioma, non-small cell lung cancer, or pancreatic cancer.

Start Date01 Mar 2003

Sponsor / Collaborator

Memorial Sloan Kettering Cancer Center

[+1]

100 Clinical Results associated with L-Alanosine

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100 Translational Medicine associated with L-Alanosine

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100 Patents (Medical) associated with L-Alanosine

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109

Literatures (Medical) associated with L-Alanosine

02 Aug 2023·Journal of the American Chemical Society

Reductases Produce Nitric Oxide in an Alternative Pathway to Form the Diazeniumdiolate Group of l-Alanosine.

Article

Author: Wang, Menghua ; Ryan, Katherine S

l-Alanosine is a diazeniumdiolate (N-nitrosohydroxylamine) antibiotic that inhibits MTAP-deficient tumor cells by blocking de novo adenine biosynthesis. Previous work revealed the early steps in the biosynthesis of l-alanosine. In the present study, we used genome mining to discover two new l-alanosine-producing strains that lack the aspartate-nitrosuccinate pathway genes found in the original l-alanosine producer. Instead, nitrate is reduced with a unique set of nitrate-nitrite reductases. These enzymes are typically used as part of the nitrogen cycle for denitrification or assimilation, and our report here shows how enzymes from the nitrogen cycle can be repurposed for the biosynthesis of specialized metabolites. The widespread distribution of nitric-oxide-producing reductases also indicates a potential for the discovery of new nitric-oxide-derived natural products.

11 Mar 2023·Oncotarget

Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss

Article

Author: Srivastava, Nimisha ; Sivapiragasam, Abirami ; Ashok Kumar, Prashanth ; Haroun, Elio ; Ross, Jeffrey ; Bou Zerdan, Maroun

INTRODUCTIONHomozygous deletion of MTAP upregulates de novo synthesis of purine (DNSP) and increases the proliferation of neoplastic cells. This increases the sensitivity of breast cancer cells to DNSP inhibitors such as methotrexate, L-alanosine and pemetrexed.MATERIALS AND METHODS7,301 cases of MBC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).RESULTS208 (2.84%) of MBC featured MTAP loss. MTAP loss patients were younger (p = 0.002) and were more frequently ER- (30% vs. 50%; p < 0.0001), triple negative (TNBC) (47% vs. 27%; p < 0.0001) and less frequently HER2+ (2% vs. 8%; p = 0.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p < 0.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p < 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% vs. 4%; p < 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB >20 mut/Mb levels in the MTAP intact MBC (p < 0.0001) and higher PD-L1 low expression (1-49% TPS) in the MTAP loss MTAP (p = 0.002) were observed.CONCLUSIONSMTAP loss in MBC has distinct clinical features with genomic alterations (GA) affecting both targeted and immunotherapies. Further efforts are necessary to identify alternative means of targeting PRMT5 and MTA2 in MTAP-ve cancers to benefit from the high-MTA environment of MTAP-deficient cancers.

01 Oct 2021·Cancer ResearchQ1 · MEDICINE

MTAP Deficiency–Induced Metabolic Reprogramming Creates a Vulnerability to Cotargeting De Novo Purine Synthesis and Glycolysis in Pancreatic Cancer

Q1 · MEDICINE

Article

Author: Zhang, Zheng ; Shi, Xiuhui ; Xu, Wenyan ; Hu, Qiangsheng ; Li, Min ; Yang, Jingxuan ; Dai, Weixing ; Zhou, Zhijun ; Ji, Shunrong ; Liu, Wensheng ; Qin, Yi ; Liu, Mengqi ; Xu, Xiaowu ; Yu, Xianjun ; Ye, Zeng ; Li, Shuo ; Fan, Guixiong ; Zhuo, Qifeng

AbstractMethylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion–mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease.Significance:This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.

100 Deals associated with L-Alanosine

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External Link

KEGG	Wiki	ATC	Drug Bank
-	L-Alanosine	-	DB05540

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Methylthioadenosine phosphorylase deletion cancer	Phase 2	US	National Cancer Institute	01 Mar 2003
Brain Cancer	Phase 2	US	Salmedix, Inc.	-
Central Nervous System Neoplasms	Phase 2	-	National Cancer Institute	-
Central Nervous System Neoplasms	Phase 2	-	Teva Pharmaceutical Industries Ltd.	-
Central Nervous System Neoplasms	Phase 2	-	University of California	-
Mesothelioma	Phase 2	US	Salmedix, Inc.	-
Non-Small Cell Lung Cancer	Phase 2	US	Salmedix, Inc.	-
Pancreatic Cancer	Phase 2	US	Salmedix, Inc.	-
Pancreatic Cancer	Phase 2	US	Salmedix, Inc.	-
Sarcoma	Phase 2	US	Salmedix, Inc.	-