XL019

Inhibitor of JAK2

Structure

Information

Protein target names: JAK2

Mechanism of action: Inhibitor

In Vitro Validations

Uniprot ID: O60674
Target Class: Protein kinase
Target SubClass: TK
Potency: IC50
Potency Value: 2.2 nM JAK2; 214 nM JAK3; 134 nM JAK1
Potency Assay: Chemiluminescence activity based assay (ATP hydrolysis)
PDB ID for probe-target interaction (3D structure): 4BBF
Structure-activity relationship: yes
Target aliases:
Tyrosine-protein kinase JAK2, JAK2, JAK2_HUMAN, JA ...

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

Comments:

Forsyth and coworkers present in the given reference the development of an aminopyrimidine based JAK2 inhibitor. Comprehensive SAR and characterization via enzymatic and cellular assays is given throughout the development story. The Probe candidate XL019 was also co-crystallized with the target and shows an interesting DFG-motif interaction with the terminal amide residue. This compound was also more intensively investigated concerning its selectivity, PK- and PD-profile.

However, the cellular activity (IC50 386nM) as well as selectivity (ca. 2-fold) for JAK2 is not as pronounced as in the biochemical assay on the isolated enzyme. Moreover, most probably due to its generic amino pyrimidine scaffold it shows moderate off target activities in a relatively small kinase panel (most prominent JAK1, FLT3, c-KIT and PDGFRB with 130 to 230 nM).

The in vivo characterization of this probe candidate is still noteworthy and it may serve as a valuable in vivo tool, but first the on- and off-target activities should be further investigated in cellular models to get a clear estimation of a valid dosage regiment without risking off-target effects.

(last updated: 26 Feb 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

Compound XL019 (CPP1230, O19, cpd 10d) appears to be a good tool molecule for JAK2 that can be used both in cellular and in vivo studies. The compound shows single-digit nM activity against JAK2 biochemically, and an EC50 of ~380 nM in a pSTAT1 cellular model.  It shows satisfactory (>50x) selectivity In a panel of 118 kinases including homologs JAK1 and JAK3, however testing in an expanded panel would be desirable. The pharmacokinetic profile in four species is adequate for oral dosing in efficacy settings, and the compound exhibits dose-dependent PD and tumor growth inhibitory efficacy in a HEL92.1.7 xenograft mouse model. The compound was advanced into Phase I clinical trials in myelofibrosis patients and discontinued after revealing central and/or peripheral neurotoxicity even at low doses. It is unclear whether this toxicity is caused by off-targets effects or a consequence of neurological JAK2 blockade.  This may have been caused by the compound’s high blood–brain barrier penetration, compounded by a long terminal half-life (~21 hrs) in humans. (https://pubmed.ncbi.nlm.nih.gov/24374145/). There is no indication that this compound was tested in a secondary pharmacology panel (e.g. CEREP) and it is recommended to generate this data.

(last updated: 12 Mar 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

This is a potent inhibitor of JAK2 with selectivity against JAK1/JAK3 and other kinases and good probe properties for interrogating the target in vitro and in vivo. Data on broad kinome selectivity is scarce, however, and does not rule out potent activity against other kinases. The original report describes two derivatives that had potent JAK activity but no activity on STAT phosphorylation in the cells (and the specific phosphorylation sites and antibodies used were not mentioned in the report). That said, while this is a good option for interrogating JAK2, caution must be exercised while interpreting cell-based results.

(last updated: 13 Mar 2021 )