MTHFD1L inhibitors(methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like inhibitors), MTHFD2 inhibitors(methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication

B-Cell Malignant NeoplasmAcute Myeloid LeukemiaHematologic Neoplasms+ [1]

Inactive Indication-

Originator Organization

The University of Sheffield

Karolinska Institutet

Active Organization

The University of Sheffield

Karolinska Institutet

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC17H18FN7O7

InChIKeyALGPVOJFIGPPPX-VIFPVBQESA-N

CAS Registry2379556-22-4

Clinical Trials associated with TH-9619

CTIS2024-519639-40-00

/ Not yet recruitingPhase 1

- TH9619-0101

Start Date-

Sponsor / Collaborator

One-Carbon Therapeutics AB

100 Clinical Results associated with TH-9619

100 Translational Medicine associated with TH-9619

100 Patents (Medical) associated with TH-9619

Literatures (Medical) associated with TH-9619

01 Dec 2023·Chemical Biology & Drug Design

Folate trapping is lethal to cancer cells

Article

Author: Rather, Gulam Mohmad

AbstractRegulation of formate flux by a key folate enzyme, MTHFD2 (methylene tetrahydrofolate dehydrogenase 2) in cancer cells remains poorly understood. Green et al. (Nature Metabolism, 2023; 5: 642–659) showed an interesting phenomenon of “folate trapping” toxicity leads to cancer cell kill using a potent inhibitor (TH9619) against the dehydrogenase and cyclohydrolase (DC) activities of cytosolic methylenetetrahydrofolate dehydrogenase 1 (cMTHFD1) and nuclear methylenetetrahydrofolate dehydrogenase 2 (nMTHFD2), but not the mitochondrial MTHFD2 (mTHFD2). But, mMTHFD2 is required for formate flow to cytosol which leads to the trapping of 10‐formyl tetrahydrofolate and causes toxicity by TH9619 treatment, to kill cancer cells expressing mMTHFD2. This article opens new avenues to be evaluated for therapeutic benefits of cancer patients where MTHFD2 shows overexpression viz‐a‐viz breast, prostate, colorectal, acute myeloid leukemia, and other cancer types.

Scientific Reports

Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L

Article

Author: Jha, Vibhu ; Eriksson, Leif A

AbstractThe mitochondrial enzyme methylenetetrahydrofolate dehydrogenase (MTHFD2) is involved in purine and thymidine synthesis via 1C metabolism. MTHFD2 is exclusively overexpressed in cancer cells but absent in most healthy adult human tissues. However, the two close homologs of MTHFD2 known as MTHFD1 and MTHFD2L are expressed in healthy adult human tissues and share a great structural resemblance to MTHFD2 with 54% and 89% sequence similarity, respectively. It is therefore notably challenging to find selective inhibitors of MTHFD2 due to the structural similarity, in particular protein binding site similarity with MTHFD1 and MTHFD2L. Tricyclic coumarin-based compounds (substrate site binders) and xanthine derivatives (allosteric site binders) are the only selective inhibitors of MTHFD2 reported till date. Nanomolar potent diaminopyrimidine-based inhibitors of MTHFD2 have been reported recently, however, they also demonstrate significant inhibitory activities against MTHFD1 and MTHFD2L. In this study, we have employed extensive computational modeling involving molecular docking and molecular dynamics simulations in order to investigate the binding modes and key interactions of diaminopyrimidine-based inhibitors at the substrate binding sites of MTHFD1, MTHFD2 and MTHFD2L, and compare with the tricyclic coumarin-based selective MTHFD2 inhibitor. The outcomes of our study provide significant insights into desirable and undesirable structural elements for rational structure-based design of new and selective inhibitors of MTHFD2 against cancer.

Chemical Biology & Drug Design

Folate trapping is lethal to cancer cells

Author: Rather, Gulam Mohmad

Regulation of formate flux by a key folate enzyme, MTHFD2 (methylene tetrahydrofolate dehydrogenase 2) in cancer cells remains poorly understood.Green et al. (Nature Metabolism, 2023; 5: 642-659) showed an interesting phenomenon of "folate trapping" toxicity leads to cancer cell kill using a potent inhibitor (TH9619) against the dehydrogenase and cyclohydrolase (DC) activities of cytosolic methylenetetrahydrofolate dehydrogenase 1 (cMTHFD1) and nuclear methylenetetrahydrofolate dehydrogenase 2 (nMTHFD2), but not the mitochondrial MTHFD2 (mTHFD2).But, mMTHFD2 is required for formate flow to cytosol which leads to the trapping of 10-formyl tetrahydrofolate and causes toxicity by TH9619 treatment, to kill cancer cells expressing mMTHFD2.This article opens new avenues to be evaluated for therapeutic benefits of cancer patients where MTHFD2 shows overexpression viz-a-viz breast, prostate, colorectal, acute myeloid leukemia, and other cancer types.

100 Deals associated with TH-9619

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
B-Cell Malignant Neoplasm	Preclinical	Sweden	Karolinska Institutet	14 May 2024
Acute Myeloid Leukemia	Preclinical	Sweden	Karolinska Institutet	28 Feb 2022
Hematologic Neoplasms	Preclinical	United Kingdom	The University of Sheffield	-
Solid tumor	Discovery	United Kingdom	The University of Sheffield	-

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