GNF-5

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.

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.

GNF-5 is an allosteric binder and a clean functional inhibitor of 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.

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.