GNF-5

Allosteric inhibitor of ABL1

Structure

Information

Protein target names: ABL1

Mechanism of action: Allosteric inhibitor

Primary References:

In Vitro Validations

Uniprot ID: P00519
Target Class: Protein kinase
Target SubClass: TK
Potency: IC50
Potency Value: 0.22 nM
Potency Assay: pyruvate kinase-lactate dehydrogenase based ABL kinase assay
PDB ID for probe-target interaction (3D structure): 3K5V
Structure-activity relationship: The structure–activity relations are fully consistent with the conformation of GNF-2 observed in the crystal structure: the trifluoromethoxy group of GNF-2 can only be accommodated at the para position; the aniline NH is required because of the formation of a water-mediated hydrogen bond to the backbone carbonyls of A433 and E462; water-mediated hydrogen bonds between the carboxamide of GNF-2 and Abl confer enhanced inhibitory activity; and the extended compound conformation is required to fit the cylindrical binding cavity.
Target aliases:
Tyrosine-protein kinase ABL1, JTK7, ABL, ABL1, ABL ...

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This probe is an allosteric inhibitor of ABL, with sound biochemical and biophysical evidence. However, its effects in cells and animals have primarily been studied in the context of combinations with an active-site inhibitor. While it does appear to have modest enzyme-inhibitory and cellular activity on its own, it is understudied as a single agent in cells and animals.

(last updated: 29 May 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

GNF-5 is an allosteric inhibitor of ABL kinase, binding to the myristate pocket near the C-terminus of the kinase domain. GNF-5 in combination with nilotinib is capable of inhibiting phosphorylation of the T315I-harboring BCR-ABL mutant in Ba/F3 cells. Further, the combination of the two compounds in a mouse model of T315I bone marrow transplantation results in complete disease remission. GNF-5, as well as next-generation inhibitors expanded by medicinal chemistry, will be useful to understand the role of allosteric inhibition of the BCR-ABL kinase in CML.

(last updated: 7 Jun 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

GNF-5 is a compound that binds to the myristate pocket of Abl was shown to act cooperatively with nilotinib and other ATP-competitive inhibitors to target the "T315I" gatekeeper mutant of Bcr-Abl. It also inhibits the closely related kinase ABL2 (ARG). Recent data showed that allosteric interactions play a key role in ABL kinase signalling. As a non-ATP competitive compound, GNF-5 is highly selective and it is therefore an ideal tool to study ABL scaffolding roles. It also provides a tool studying ABL mutations resistant to ATP mimetic compounds.

(last updated: 4 Nov 2020 )

SERP Comments:

GNF-5 is an allosteric binder and a clean functional inhibitor or Bcr-Abl in vitro and in cells. The potency of GNF-5 alone is modest and it is best used in combination with an orthosteric inhibitor where convincing data shows a synergistic effect in cells and in vivo. While this is sensible and probably the most important way in which compounds like GNF-5 will be studied, it is important to point out that some of the single agent data is limited. In cells it would appear that certainly in a uM range, solid inhibition of the enzymatic function can be achieved. Some of the in vivo data that is referencing a 20 mpk dose perhaps provides insufficient inhibition. It appears that minimally 100 mpk b.i.d. are likely necessary to drive a strong single agent response, but without further data and PKPD modeling it is difficult to assess whether full target engagement can be expected even at such a high dose. In cells GNF-5 seems to be clearly a great tool compound and in vivo the best characterized option with the caveat that levels of TE likely need to be monitored and higher doses are required for use as single agent.

(last updated: 4 Nov 2020 )