CSF1R Program: Selective Kinase Inhibitors for Oncology and Inflammation

Colony-stimulating factor 1 receptor (CSF1R) is a cell surface protein encoded in the human body using the CSF1R gene (also known as c- FMS). This is a receptor for cytokines called colony-stimulating factor 1.

Genomics

The gene is located on the long arm of chromosome 5 (5q32) on the (minus) Creek chain. This is 60.002 kb in length. The encoded protein has 972 amino acids and a predicted molecular weight of 107.984 kilo Daltons. The first intron of the CSF1R gene contains the transcriptionally inactive ribosomal protein L7 of the processed pseudogene, oriented in the opposite direction to the CSF1R gene.

The encoded protein is one type of pass-through membrane protein and acts as a receptor for colony-stimulating factor 1, a cytokine that controls the production, differentiation and function of macrophages. This receptor mediates most of the biological effects of this cytokine. Ligand binding activates CSF1R through the process of oligomerization and transphosphorylation. The encoded protein is a transmembrane receptor tyrosine kinase and a member of the CSF1 / PDGF receptor tyrosine-protein kinase family.

Clinical significance

Elevated levels of CSF1R1 are found in microglia in Alzheimer’s disease and after traumatic brain injury. Increased receptor expression causes microglia to become more active. Both CSF1R and its ligand colony-stimulating factor 1 play an important role in the development of the mammary gland and may be involved in the process of breast carcinogenesis.

Mutations in CSF1R are associated with chronic myelomonocytic leukemia and type M4 acute myeloid leukemia.

Mutations in the tyrosine kinase domain have been associated with hereditary diffuse leukoencephalopathy with spheroids.

As a target for a drug

Since CSF1R is overexpressed in many cancers and tumor-associated macrophages (TAMs), CSF1R inhibitors (and CSF1 inhibitors) have been studied for many years as a possible treatment for cancer or inflammatory diseases. In 2017, CSF1R inhibitors in clinical trials include: Pexidartinib, PLX7486, Arry-382, JNJ-40346527, BLZ945, Emactuzumab, AMG820, IMC-CS4. (PD-0360324 and MCS110 are CSF1 inhibitors).

Another CSF1R inhibitor that targets / depletes TAM is Cabiralizumab (cabira; FP-008), which is a monoclonal antibody, and in early clinical trials for metastatic pancreatic cancer.

Interactions

CSF1R interacts with:

• Cbl gene;
• FYN;
• Grb2;
• A suppressor of cytokine signaling 1 – this receptor is also associated with MOB cells.