GNF-5837

Inhibitor of NTRK1, NTRK2, NTRK3

Structure

Information

Protein target names: NTRK1, NTRK2, NTRK3

Mechanism of action: Inhibitor

Recommended in-cell concentration:
up to 100 nM

Reviewer recommended in-cell concentration: 50-500 nM

In Vitro Validations

Uniprot ID: P04629
Target Class: Kinase
Target SubClass: TK
Potency: IC 50
Potency Value: 8 nM
Potency Assay: HTRF Assay
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: yes
Target aliases:
High affinity nerve growth factor receptor, TRKA, ...

DOI Reference: 10.1021/ml200261d

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 26 Jul 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

There are more well-characterized tools, in particular Laratrectinib which is both approved for human use and better profiled for selectivity against more kinases (link)or perhaps clinical compounds AZD7451.  

Cell Concentration notes: Fig1 of the 2nd reference shows a plateau of activity from 50-500 nM in GOT1 cell.

Ref1 demonstrates sufficient IV and PO exposure for human tumor xenograft studies plus demonstrated efficacy. However, given the ~86% similarity between human and rat/mouse TRKA, I would recommend confirming rat or mouse potency comparable to humans before using rats or mice as an efficacy model in a non-human xenograft study

(last updated: 4 Aug 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Together the two reference documents provide acceptable evidence that cell-based and organism-based anticancer activity may be due to pan TRK inhibition, and the E-R Cancer study shows evidence of target inhibition in cells. However, like many kinase inhibitor studies, more evidence may be required to be certain that in vivo efficacy reflects target engagement and further, also like many kinase inhibitor studies, in the absence of an entirely comprehensive kinase profile and other profiling (including tubulin for example), some caution is still advised in assuming that all cell-based activity arises from pan Trk inhibition since the kinase inhibitor field continues to surprise. Finally, it would be useful to identify a negative control – perhaps an N-methylated analogue or better, one with the CF3 moved to the para position (if all Trk activity is lost), and to use this in all studies.

(last updated: 26 Aug 2021 )