TH9619

TH9619 : Inhibitor of MTHFD1, MTHFD2, MTHFD2L

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

(1 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Probe TH9619 is in the process of SERP review.

Please continue to check back for new reviews and commentary.

Information

MTHFD1
MTHFD2
MTHFD2L

Inhibitor

up to 1 uM

In Vitro Validations

Uniprot ID: P11586

Target Class: Enzyme

Target SubClass: Dehydrogenase

Potency: IC50

Potency Value: 16 nM

Potency Assay: biochemical activity assays

PDB ID for probe-target interaction (3D structure): 6S4F

Target aliases:

C-1-tetrahydrofolate synthase, cytoplasmic, MTHFD, ...

DOI Reference: 10.1038/s43018-022-00331-y

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): DSF-based selectivity screen of TH9619 12 µM against a curated library of 44 kinases, using staurosporine as a positive control. Selectivity of TH9619 10 µM against the SafetyScreen44 panel from Eurofins. DOI: 10.1038/s43018-022-00331-y

Potency assay, off target (cells): no stabilization of mitochondrial MTHFD2 using CETSA on purified subcellular fractions of mitochondria

I have extra information to add

SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

TH9619 is a well-characterized double-digit nanomolar inhibitor for MTHFD2, MTHFD2L and MTHFD1. Compared to previously described inhibitors such as LY345899 or DS18561882 it shows significantly improved potency. TH9619 was profiled in a DSF-based assay against 44 kinases and in a broader safety panel including another 44 targets. In a CETSA assay TH9619 showed cellular target engagement despite its high polarity and the high number of hydrogen bond donors assuming active cellular uptake via transporters. In addition, X-ray co-crystal structures of close analogues are available. Several in vitro studies were performed to investigate the role of MTHFD2 inhibitors in cancer. TH9619 showed comparable inhibition between human and mouse MTHFD2 and its pharmacokinetic profile with a short half-life but good tolerability allowed twice-daily dosing in a mouse efficacy study.

(last updated: 8 Aug 2024 )