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 NeoplasmHematologic NeoplasmsSolid tumor

Inactive Indication-

Originator Organization

The University of Sheffield

Karolinska Institutet

Active Organization

The University of Sheffield

Karolinska Institutet

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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.

Nature Metabolism

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Article

Author: Johansson, Annika I ; Ramos, Louise ; Ghahe, Elahe Kamali ; Viry, Elodie ; Green, Alanna C ; Meiser, Johannes ; Homan, Evert ; Mortusewicz, Oliver ; Paggetti, Jérôme ; Meyers, Marianne ; Borhade, Sanjay ; Kiweler, Nicole ; Lesur, Antoine ; Jemth, Ann-Sofie ; Chalkiadaki, Christina ; Loseva, Olga ; Helleday, Thomas ; Marttila, Petra ; Hodek, Ondřej ; Jiménez-Alonso, Julio J ; Wiita, Elisée ; Cookson, Victoria ; Letellier, Elisabeth ; Slipicevic, Ana ; Sandberg, Lars ; Moussay, Etienne ; Bonagas, Nadilly ; Eiden, Kim ; Long, Maeve ; Bernardin, François ; Frödin, Morten ; Vallin, Karl S A ; Sørensen, Claus Storgaard ; Henriksson, Martin

AbstractCancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

100 Deals associated with TH-9619

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
B-Cell Malignant Neoplasm	Preclinical	SE	Karolinska Institutet	14 May 2024
Hematologic Neoplasms	Preclinical	GB	The University of Sheffield	-
Solid tumor	Discovery	GB	The University of Sheffield	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

TH-9619

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation