STM2457

Inhibitor, SAM competitive of METTL3

Structure

Information

Protein target names: METTL3

Mechanism of action: Inhibitor, SAM competitive

Recommended in-cell concentration:
up to 10 uM

In Vitro Validations

Uniprot ID: Q86U44
Target Class: Epigenetic
Target SubClass: Methyltransferase
Potency: IC50
Potency Value: 16.9 nM
Potency Assay: METTL3/14 RF/MS methyltransferase assay
PDB ID for probe-target interaction (3D structure): 7O2I
Structure-activity relationship: no
Target aliases:
N6-adenosine-methyltransferase catalytic subunit, ...

DOI Reference: 10.1038/s41586-021-03536-w

Uniprot ID: Q86U44
Target Class: Epigenetic
Target SubClass: Methyltransferase
Potency: Kd
Potency Value: 1.4 nM
Potency Assay: SPR
PDB ID for probe-target interaction (3D structure): --
Target aliases:
N6-adenosine-methyltransferase catalytic subunit, ...

DOI Reference: 10.1038/s41586-021-03536-w

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

Comments:

STM2457 is a best-in-class probe at present. I think it is great to use in cell assays since potency and binding are good and consistent with cellular thermal shift. The PK details are limited. It is difficult to understand in vivo use without knowing protein binding and really understanding how much free drug gets to site of action/target occupancy in vivo. A 50mpk dose is quite high so for in vivo use I see this as a molecule at the start of lead generation rather than a typical lead optimisation molecule which would ideally be <10mpk and be fully annotated with all PK parameters. At 50mpk, broader selectivity profiling beyond kinases (all target classes and toxicity panels e.g. ion channels) would be important.

(last updated: 20 May 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

STM2457 is a potent and selective probe with demonstrated on target cell activity. The compound was shown to be active against leukemia cell lines and leukemia PXD models.

(last updated: 4 Jun 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

Valuable first-in-class chemical probe. Robust characterization of specific target engagement is provided. Selectivity within narrow and broad enzyme families demonstrated. The compound is suitable for in vivo work with IP administration in mouse but note that detailed PK data were not provided. STM2120 is a useful but not ideal negative control – it is noticeably smaller than STM2457 and is missing a substituent making important lipophilic and polar interactions with the protein.

(last updated: 25 Jun 2021 )