lometrexol (T-64) News - LARVOL Sigma

|||||||||| Venclexta (venetoclax) / Roche, AbbVie, ME-344 / MEI
Preclinical, Journal: Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro. (Pubmed Central) - Jan 29, 2024
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.

|||||||||| lometrexol (T-64) / Amgen
Journal: Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations. (Pubmed Central) - May 30, 2023
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.

|||||||||| lometrexol (T-64) / Amgen
Journal, Metastases: 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 ER? expressing primary and metastatic invasive ductal carcinoma. (Pubmed Central) - May 9, 2023
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.

|||||||||| Folotyn (pralatrexate) / Aurobindo, Tomudex (raltitrexed) / Pfizer, AstraZeneca, lometrexol (T-64) / Amgen
Review, Journal: Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities. (Pubmed Central) - Oct 21, 2022
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.

|||||||||| lometrexol (T-64) / Amgen
Journal: VGLL3 increases the dependency of cancer cells on de novo nucleotide synthesis through GART expression. (Pubmed Central) - Jun 22, 2022
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.

|||||||||| Venclexta (venetoclax) / Roche, AbbVie, ME-344 / MEI
A Novel Isoflavone, ME-344, Enhances Venetoclax Antileukemic Activity Against AML Via Suppression of Oxidative Phosphorylation and Purine Biosynthesis (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3856;
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.

|||||||||| methotrexate / Generic mfg.
Journal: Molecular mechanism of c-Myc and PRPS1/2 against thiopurine resistance in Burkitt's lymphoma. (Pubmed Central) - Apr 30, 2021
However, there remains a subgroup of patients with lactate dehydrogenase higher than four times of the normal value (4N) for whom novel treatments are needed. Notably, we found that the combination of thiopurines and the phosphoribosylglycinamide formyltransferase (GART) inhibitor lometrexol could serve as a therapeutic strategy to overcome thiopurine resistance in BL.



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