lometrexol (T-64) / Eli Lilly, Amgen, Dana-Farber Cancer Institute - LARVOL DELTA

Purinosomes and Lysosomes Interact to Maintain the Purine Pools. (PubMed, Int J Biochem Cell Biol) - "By combining in-cell stable isotope incorporation assay with quantitative metabolomics we show: cellular uptake of external purines and their internal generation are equivalent; an upregulation in lysosome biogenesis that functions in response to purine deficiency caused by methotrexate (MTX) and lometrexol (LTX) treatment. This leads to increased RNA digestion as visualized by a newly developed intracellular RNA-FRET oligo assay. Interestingly, downregulation of lysosomal RNase activity through knockdown of RNAseT2 increased RNA accumulation and a compensating increase in DNPB."

Journal • Oncology • RNASET2

A phase II trial to evaluate clinical efficacy, pharmacodynamics and exploratory analysis of pemetrexed in relation to MLL4 and UTX alteration status in patients with relapsed/refractory metastatic urothelial carcinoma and other solid tumors. (ASCO 2025) - P2 | "We demonstrated sensitivity to lometrexol, which targets the enzyme GART (glycinamide ribonucleotide formyltransferase), in animal models of CRC and BLCA with MLL4 truncation. Correlative studies will be carried out alongside the study to assess for mechanisms of resistance to pemetrexed. Molecular analysis of ctDNA will be performed on plasma for both arms and for plasma and urine for cohort A (bladder cohort) at pre-determined time points during treatment."

Clinical • Metastases • P2 data • PK/PD data • Bladder Cancer • Colorectal Cancer • Oncology • Solid Tumor • Urothelial Cancer • KDM6A • KMT2D

Inhibition of Purine Metabolism Promotes the Differentiation of Neuroblastoma Driven by MYCN. (PubMed, Cancer Med) - "These findings establish purine metabolic enzyme inhibition as a viable therapeutic strategy to induce differentiation and attenuate tumor progression in high-risk MYCN-amplified NBs."

Journal • Neuroblastoma • Oncology • Solid Tumor • MYCN

Therapeutic targeting de novo purine biosynthesis driven by β-catenin-dependent PPAT upregulation in hepatoblastoma. (PubMed, Cell Death Dis) - "Our findings suggest that HB patients harboring activated β-catenin mutations and consequent DNPS upregulation, may be treated efficaciously with DNPS enzyme inhibitors like lometrexol. These novel findings bear major therapeutic implications for targeted precision medicine of HB."

Journal • Hepatoblastoma • Hepatology • Oncology • Solid Tumor • CTNNB1

Impact of MTHFD2 Expression in Bladder/Breast Cancer and Screening of Its Potential Inhibitor. (PubMed, ACS Omega) - "Similar scaffold commercial drugs leucal (LEU), epirubicin (EPI), and lometrexol also displayed strong binding to the active site of MTHFD2...The interaction of breast cancer serum with high expression of MTHFD2 also showed an increase in binding of epirubicin in the presence of leucovorin...Further experimental studies are required to establish the potential mode of inhibition of the novel small ligands. Future in vivo trials may validate the effectiveness of the combinatorial therapy."

Journal • Bladder Cancer • Breast Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MTHFD2

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro. (PubMed, Biochem Pharmacol) - "Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy...Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines...In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations. (PubMed, J Clin Invest) - "Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KMT2C • KMT2D

A functional genetic screen for metabolic proteins unveils GART and the de novo purine biosynthetic pathway as novel targets for the treatment of luminal A ERα expressing primary and metastatic invasive ductal carcinoma. (PubMed, Front Endocrinol (Lausanne)) - "Moreover, the GART inhibitor lometrexol (LMX) and drugs approved for clinical treatment of primary and metastatic BC (4OH-tamoxifen and the CDK4/CDK6 inhibitors) exert synergic antiproliferative effects in BC cells. In conclusion, GART inhibition by LMX or other inhibitors of the de novo purine biosynthetic pathway could be a novel effective strategy for the treatment of primary and metastatic BCs."

Journal • Metastases • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CDK6 • ER

Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities. (PubMed, Molecules) - "In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed."

Journal • Review • Oncology

VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression. (PubMed, J Cell Biochem) - "Lometrexol also repressed the proliferation of these breast cancer cells, whereas addition of inosine monophosphate, an important metabolite downstream of GART, rescued this repression. Taken together, these results suggest that VGLL3 induces GART expression and thereby confers de novo nucleotide-dependent cell proliferation in cancer cells."

Journal • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • VGLL3

A Novel Isoflavone, ME-344, Enhances Venetoclax Antileukemic Activity Against AML Via Suppression of Oxidative Phosphorylation and Purine Biosynthesis (ASH 2021) - "Interestingly, inhibition of this pathway by the purine biosynthesis inhibitor lometrexol, also synergistically enhanced apoptosis in AML cells induced by venetoclax. Taken together, these results suggest that ME-344 suppresses OXPHOS and the purine biosynthesis pathway to enhance the antileukemic activity of venetoclax against AML. Further in-depth mechanistic studies into the suppression of purine biosynthesis and OXPHOS, as well as studies of ME-344 and venetoclax against cytarabine-resistant AML in a mouse model are warranted."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • MCL1