Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous <i>MTAP</i> Deletion

Konteatis, Zenon; Travins, Jeremy; Größ, Stefan; Marjon, Katya; Barnett, Amelia; Mandley, Everton; Nicolay, Brandon; Nagaraja, Raj; Chen, Yue; Sun, Yabo; Liu, Zhixiao; Yu, Jie; Ye, Zhixiong; Jiang, Fan; Wei, Wentao; Cheng, Fang; Gao, Yi; Kalev, Peter; Hyer, Marc L.; DeLaBarre, Byron; Jin, Lei; Padyana, Anil K.; Dang, Lenny; Murtie, Joshua; Biller, Scott A.; Sui, Zhihua; Marks, Kevin M.

doi:10.1021/acs.jmedchem.0c01895

Cited by 56 publications

(56 citation statements)

References 32 publications

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“…Efforts have been made to target methionine metabolism in tumors with deletion of methylthioadenosine phosphorylase ( MTAP ) ( 137 ), which is often co-deleted with the tumor suppressor CDKN2A. Deletion of MTAP results in accumulation of its substrate, methylthioadenosine, which has been shown to be an endogenous inhibitor of protein arginine methyltransferase 5 (PRMT5).…”

Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

“…AG-270 is an orally active inhibitor of MAT2A, which dose-dependently reduced SAM levels in tumor and blocked tumor growth in a pancreatic xenograft model ( 137 ). The preliminary results from an ongoing, first-in-human, phase I trial of AG-270 in patients with advanced solid tumors with homozygous deletion of MTAP showed reduction in plasma SAM across a range of doses, demonstrating target engagement ( 139 ).…”

Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

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Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.

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Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

Section: Metabolic Inhibitors In Clinical Trialsmentioning

confidence: 99%

Clinical development of metabolic inhibitors for oncology

Lemberg¹,

Gori²,

Tsukamoto³

et al. 2022

Journal of Clinical Investigation

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show abstract

“…Furthermore, the cells showed reduced proliferation and PRMT5 methylation activity upon depletion of MAT2A. A selective MAT2A inhibitor able to block the growth of MTAP-null cells both in tissue culture and xenograft tumors has been recently proposed for assessment in phase 1 clinical trial [64].…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants and Somatic Alterations Associated with MITF-E318K Germline Mutation in Melanoma Patients

Vergani

Frigerio

Dugo

et al. 2021

Genes

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The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients.

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“…MTAP and p16/CDKN2A are two adjacent genes located at the 9p21 locus and homozygously co-deleted in approximately 15% of all human cancers [ 123 ]. Importantly, MAT2A inhibitors have anti-proliferative activity in MTAP-deleted cancer cells and tumors [ 162 ], a result that prompted the development of a phase I clinical trial using MAT2A inhibitors (ClinicalTrials.gov NCT03435250) [ 163 ].…”

Section: Potential Therapeutic Uses Derived From Cobalamin Avidity An...mentioning

confidence: 99%

Diagnostic and Therapeutic Perspectives Associated to Cobalamin-Dependent Metabolism and Transcobalamins’ Synthesis in Solid Cancers

2022

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Cobalamin or vitamin B12 (B12) is a cofactor for methionine synthase and methylmalonyl-CoA mutase, two enzymes implicated in key pathways for cell proliferation: methylation, purine synthesis, succinylation and ATP production. Ensuring these functions in cancer cells therefore requires important cobalamin needs and its uptake through the transcobalamin II receptor (TCII-R). Thus, both the TCII-R and the cobalamin-dependent metabolic pathways constitute promising therapeutic targets to inhibit cancer development. However, the link between cobalamin and solid cancers is not limited to cellular metabolism, as it also involves the circulating transcobalamins I and II (TCI or haptocorrin and TCII) carrier proteins, encoded by TCN1 and TCN2, respectively. In this respect, elevations of B12, TCI and TCII concentrations in plasma are associated with cancer onset and relapse, and with the presence of metastases and worse prognosis. In addition, TCN1 and TCN2 overexpressions are associated with chemoresistance and a proliferative phenotype, respectively. Here we review the involvement of cobalamin and transcobalamins in cancer diagnosis and prognosis, and as potential therapeutic targets. We further detail the relationship between cobalamin-dependent metabolic pathways in cancer cells and the transcobalamins’ abundancies in plasma and tumors, to ultimately hypothesize screening and therapeutic strategies linking these aspects.

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Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion

Cited by 56 publications

References 32 publications

Clinical development of metabolic inhibitors for oncology

Clinical development of metabolic inhibitors for oncology

Genetic Variants and Somatic Alterations Associated with MITF-E318K Germline Mutation in Melanoma Patients

Diagnostic and Therapeutic Perspectives Associated to Cobalamin-Dependent Metabolism and Transcobalamins’ Synthesis in Solid Cancers

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