PLX647 is a Highly Specific and Orally Active Dual FMS and KIT Kinase Inhibitor

PLX647 is a Highly Specific and Orally Active Dual FMS and KIT Kinase Inhibitor

Inflammation and cancer are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and cancer cells. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS, CSF1R) is a member of the PDGFR family of class-III receptor tyrosine kinases. The two known ligands of FMS are M-CSF or CSF-1 and IL-34. They activate signaling through the receptor in a similar fashion but differ in their developmental and tissue-specific expression patterns. The stem cell factor (SCF) receptor v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog KIT is another member of the PDGFR family. Mutational activation of KIT has been well-documented in a number of cancers. Thus, FMS and KIT are two hematopoietic cell surface receptors. They regulate the development and function of macrophages and mast cells, respectively. In this study, PLX647 is an orally active and specific dual FMS and KIT kinase inhibitor.

PLX647 is a Highly Specific and Orally Active Dual FMS and KIT Kinase Inhibitor 2020 08 20 - PLX647 is a Highly Specific and Orally Active Dual FMS and KIT Kinase Inhibitor

PLX647 inhibits FMS and KIT kinase with IC50s of 28 and 16 nM. PLX647 shows selectivity for FMS and KIT over a panel of 400 kinases at a concentration of 1 μM except FLT3 and KDR.

In vitro, PLX647 potently inhibits the proliferation of BCR-FMS cells, with an IC50 of 92 nM. A corresponding Ba/F3 cell line expressing BCR-KIT is also quite sensitive to PLX647 (IC50=180 nM). It also inhibits endogenous FMS and KIT, as demonstrated by inhibition of the ligand-dependent cell lines M-NFS-60 (IC50=380 nM) and M-07e (IC50=230 nM). Moreover, it potently inhibits the growth of FLT3-ITD-expressing MV4-11 cells (IC50=110 nM). In addition, it displays minimal inhibition of the proliferation of Ba/F3 cells expressing BCR–KDR (IC50=5 μM). Meanwhile, PLX647 inhibits osteoclast differentiation with an IC50 of 0.17 μM.

PLX647 reduces macrophage accumulation in UUO kidney and blood monocytes. PLX647 educes LPS-induced TNF-α and IL-6 release. It also results in significant inhibition of TRAP5b immunostaining and bone osteolysis. PLX647 is able to prevent bone damage by the tumor cells. In addition, PLX647 shows effects on collagen-induced arthritis.

In summary, PLX647 is a highly specific dual FMS and KIT kinase inhibitor. The dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and cancer.

Reference:

Zhang C, et al. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5689-94.

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