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URMC-099

Inhibitor of MAP3K9, MAP3K10, MAP3K11

Structure

Information

  • MAP3K9
  • MAP3K10
  • MAP3K11
  • Inhibitor
  • N/A

In Vitro Validations

Uniprot ID: P80192
Target Class: Kinase
Target SubClass: TKL
Potency: IC 50
Potency Value: 19 nM
Potency Assay: Kinase assay
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: In our SAR studies, we observed that the pyrrolo NH and the pyridine nitrogen of the scaffold were required for potency. In addition, for the side chains, having an aromatic group such as an indole, aniline, or phenol was associated with high in vitro enzyme inhibition potency as they provided a hydrogen bond donor from the para position of an aromatic ring.
Target aliases:
Mitogen-activated protein kinase kinase kinase 9, ...

DOI Reference: 10.1021/jm401094t

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 LRRK2 11 nM, DLK 150 nM, ABL T315I 3 nM, FLT3 4 nM
Potency assay (off target): In ScanMax Assay (DiscoveRx), URMC-099 inhibited 111 of 442 kinases >90% at 1 uM. In radiometric assay, URMC-099 inhibited 36 of 342 kinases >99% at 1 uM.
Probe Selectivity in Vitro:
In ScanMax Assay (DiscoveRx), URMC-099 inhibited 111 of 442 kinases >90% at 1 uM. In radiometric assay, URMC-099 inhibited 36 of 342 kinases >99% at 1 uM. Negligible activity against the CYP P450s 2D6, 3A4, 2C9 (IC50s > 10 uM).
Probe Selectivity in Cell:
Negligible activity against hERG in automated CEREP whole-cell patch clamp assays, IC50 = 21 uM.
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This is a promiscuous kinase inhibitor with significant off-target activity.

(last updated: 20 Jun 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This compound is an orally bioavailable, brain-penetrant inhibitor of MLK, but it show poor selectivity against many other protein kinases.

(last updated: 24 Jun 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This compound is rather promiscuous and targets several kinases other than the MLK family with equal or even greater potency.

(last updated: 1 Jul 2016 )

Portal Comments

In a 2023 study, Hu et al. evaluated URMC-099 in live-cell assays for Phospholipidosis induction, cautioning about adverse effects at concentrations near 1 uM. (DOI:10.1016/j.chembiol.2023.09.003)

(last updated: 7 Nov 2023)