XMD-12

Inhibitor of AURKA, AURKB, AURKC

Structure

Information

  • AURKA
  • AURKB
  • AURKC
  • Inhibitor
  • up to 1 uM

In Vitro Validations

Uniprot ID: O14965
Target Class: Kinase
Target SubClass: cell cycle-regulated kinase
Potency: IC 50
Potency Value: 5.6 nM
Potency Assay: Invitrogen biochemical assay
PDB ID for probe-target interaction (3D structure): 3ZTX
Structure-activity relationship: yes
Target aliases:
Aurora kinase A, STK6, STK15, IAK1, BTAK, AYK1, AU ...

DOI Reference: 10.1021/cb200305u

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency end-point : IC50 LRRK2 30.5 nM , LRRK2 (G2019S) 10.7 nM
Potency assay (off target): Invitrogen biochemical assay
Probe Selectivity in Vitro:

Profiled using KINOMEscan @ 1 uM across a panel of 442 kinases: revealed sub-100 nM IC50 against DCAMKL2, LRRK2, NUAK1, and TAOK1. Potent biochemical inhibitor of LRRK2 (IC50 = 30.5 nM), this should be considered if it is being employed in scenarios where LRRK2 is expressed. DCAMKL2 87.7 nM; MAP3K2 155 nM; MAP3K3 120 nM; NUAK1 52.2 nM; TAOK2 54.3 nM

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

XMD-12 has good kinome-wide selectivity with DCAMKL2, LRRK2, NUAK1 and TAOK1 being the only off targets below 100 nM, but target engagement and cellular inhibition has not been demonstrated for these off targets. At low concentration (100 nM), this pan-Aurora Inhibitor induces a SAC silencing phenotype suggesting that phenotypically, XMD-12 behaves like an pan-Aurora Inhibitor. Due to the known off targets and the lack of a negative control, I recommend however using additional Aurora inhibitors such as VX-680 or MLN8054 as controls.

(last updated: 18 Oct 2020 )

SERP Ratings

In Cell Rating

SERP Comments:

Compound 1 complements the set of known selective Aurora inhibitors and is among the most kinase selective pan-Aurora inhibitor reported.  The established pan-Aurora inhibitor VX680 appears to have more off-target activities, such as Flt-3 and Abl, and the panel used in its original publication was significantly smaller (58 kinases).  While compound 1 is a relatively kinase selective compound, it is not free of significant kinase off-target activities, e.g. LRRK2 IC50 = 30 nM.  Apart from the kinases that IC50s were determined for, the Ambit panel had numerous additional hits that were not followed up on in an IC50 screen (ERK5, TNK1, RET, FGR, CSF1R), and IC50 data for these kinases would provide additional confidence in adequate selectivity of this probe. Antiproliferation cellular EC50s in three cancer cell lines (HCT116, HT29, HeLa) are between 10 and 55 nM, which seems more potent than what would be expected based on its biochemical Aurora B IC50, in light of ATP concentrations >30x higher in cells, serum binding, etc. but the observed small shift is in line with other reported Aurora inhibitors. Use of this probe is limited to cellular applications as in vivo use of this compound was not reported, possibly due to ADME property shortcomings, but no further information is provided in the corresponding paper.

(last updated: 2 Dec 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 14 Apr 2021 )