Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor

Abstract

Inflammation and cancer, two therapeutic areas historically addressed by separate drug discovery efforts, are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and cancer cells. Agents that target specific compartments of the immune system, therefore, not only bring new disease modifying modalities to inflammatory diseases, but also offer a new avenue to cancer therapy by disrupting immune components of the microenvironment that foster tumor growth, progression, immune evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) are two hematopoietic cell surface receptors that regulate the development and function of macrophages and mast cells, respectively. We disclose a highly specific dual FMS and KIT kinase inhibitor developed from a multifaceted chemical scaffold. As expected, this inhibitor blocks the activation of macrophages, osteoclasts, and mast cells controlled by these two receptors. More importantly, the dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and cancer.cancer bone metastasis | CSF1R | rheumatoid arthritis | scaffold-based drug design

Colony-Stimulating Factor 1 Receptor Antagonists Sensitize Human Immunodeficiency Virus Type 1-Infected Macrophages to TRAIL-Mediated Killing

“…1b and 2c and d). Therefore, no cellular toxicities were observed in vitro at the tested concentrations, as others have previously shown (38). The CSF-1R antagonists PLX647, PLX3397, and PLX5622 impacted the viability of infected macrophages and their ability to support HIV-1 replication at 10 M. Lower concentrations (1 M and 3 M) did not result in antiviral response in macrophages (data not shown).…”

“…We assessed them in parallel with a compound (PLX03) that does not have inhibitory activity against the CSF-1R in either biochemical or cell-based assays but is similar to the CSF-1R antagonists in molecular weight and composition. PLX03 does not have appreciable activity against other kinases but has the same 7-azaindole scaffold that is the active component of numerous kinase inhibitors (38) and is present in the CSF-1R antagonists assessed in this study. As PLX03 does not exhibit antagonism to CSF-1R activation and does not impact HIV activity in macrophages, it demonstrates that the impact of these agents on HIV in macrophages was mediated by their effect on CSF-1R phosphorylation rather than via potential nonspecific, off-target effects of the agents on a process unrelated to CSF-1R phosphorylation.…”

“…Depleting HIV-1-infected macrophages may result in the decline of cytokine and chemokine production and, hence, reduction of inflammation and immune cell recruitment, each of which has been associated with poor prognoses and ongoing viral replication (40). CSF-1R antagonists have been shown to reduce TNF-␣ in rodent models (38,41). Reductions in interleukin 6 (IL-6) and inflammatory cell infiltration were also observed with PLX647 (38) and a decrease in IL-1␤ levels with PLX5622 and PLX3397 (41,42).…”

Tumor-Associated Macrophages: Implications in Cancer Immunotherapy

“…This has been translated to a first-inhuman Phase I/II study of BLZ945 alone or in combination with PDR001, a monoclonal antibody against PD-1 in advanced solid tumors (NCT02829723). Another agent, PLX3397, selectively inhibits CSF1R and two other tyrosine kinase receptors KIT and FLT3 [84]. Blockage of CSF1R with PLX3397 not only improved the efficacy of adoptive cell therapy through inhibition of immunosuppressive macrophage recruitment and activation in murine melanoma but also potentiated the response of xenograft glioblastoma to ionizing radiation (IR) by preventing differentiation and protumoral activation of IR-recruited monocytes in mice [85,86].…”

Tenosynovial Giant Cell Tumor: Better molecular understanding revolutionizes treatment outcome

“…Tap et al modified the molecule of an inhibitor (PLX647) of CSF1R to produce a new compound, PLX3397, which is a more potent inhibitor that binds to and locks the receptor in an inactive conformation [13,14] . At a dose of 1000 mg per day, 23 patients exhibited a significant response rate (52%), and even more impressively, a median duration of disease control exceeding 8 months.…”