Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors

Ramachandran, Sreekanth; Jadhavar, Pradeep S.; Miglani, Sandeep K.; Singh, Manvendra; Kalane, Deepak P.; Agarwal, Anil K.; Sathe, Balaji D.; Mukherjee, Kakoli; Gupta, Ashu; Haldar, Srijan; Raja, Mohd.; Singh, Siddhartha; Pham, Son M.; Chakravarty, Sarvajit; Quinn, Kevin P.; Belmar, Sebastián; Higgs, Christopher; Bernales, Sebastián; Herrera, Francisco; Rai, Roopa

doi:10.1016/j.bmcl.2017.03.064

Cited by 17 publications

(10 citation statements)

References 18 publications

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“…The ability of caspase deletion or inhibition to prevent the development of bleomycin-induced lung fibrosis is associated with changes in the cell surface markers of lung-infiltrating macrophages and the level of cytokines detected in the broncho-alveolar lavage, suggesting modification in the polarization of these cells. Pan-caspase inhibition thus appears as an alternative strategy to monoclonal antibodies and small molecule inhibitors of CSF1 and CSF1R [ 10 , 62 ], STAT3 inhibitory molecules [ 63 ], DNA vaccine against the “M2”-associated asparaginyl endopeptidase legumain [ 64 ] and other strategies [ 65 ] to modulate the polarization of macrophages recruited in damaged tissues.…”

Section: Discussionmentioning

confidence: 99%

Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues

Solier

Mondini

Meziani

et al. 2023

IJMS

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Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we demonstrate that activated caspase-3 and caspase-7 are located to the vicinity of the mitochondria in CSF1-treated human monocytes. Active caspase-7 cleaves p47phox at aspartate 34, which promotes the formation of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex NOX2 and the production of cytosolic superoxide anions. Monocyte response to CSF-1 is altered in patients with a chronic granulomatous disease, which are constitutively defective in NOX2. Both caspase-7 down-regulation and radical oxygen species scavenging decrease the migration of CSF-1-induced macrophages. Inhibition or deletion of caspases prevents the development of lung fibrosis in mice exposed to bleomycin. Altogether, a non-conventional pathway that involves caspases and activates NOX2 is involved in CSF1-driven monocyte differentiation and could be therapeutically targeted to modulate macrophage polarization in damaged tissues.

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Section: Discussionmentioning

confidence: 99%

Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues

Solier

Mondini

Meziani

et al. 2023

IJMS

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“…Van der Wildt et al 46 found that compound 3 had a CSF1R inhibitory potency of 2.7 ± 0.4 nM, in good accord with a previously reported value (Table 2). 66 However, in contrast with findings in a prior study, they found that 3 has poor selectivity toward CSF1R over closely related c-KIT and PDGFRβ kinases (IC 50 , 4.5 and 6.3 nM, respectively).…”

Section: Pyridines 231 [ 11 C]2mentioning

confidence: 99%

Candidate Tracers for Imaging Colony-Stimulating Factor 1 Receptor in Neuroinflammation with Positron Emission Tomography: Issues and Progress

Altomonte,

Pike

2023

ACS Pharmacol. Transl. Sci.

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The tyrosine kinase, colony-stimulating factor 1 receptor (CSF1R), has attracted attention as a potential biomarker of neuroinflammation for imaging studies with positron emission tomography (PET), especially because of its location on microglia and its role in microglia proliferation. The development of an effective radiotracer for specifically imaging and quantifying brain CSF1R is highly challenging. Here we review the progress that has been made on PET tracer development and discuss issues that have arisen and which remain to be addressed and resolved.

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“…The receptor tyrosine kinase (RTK) signaling pathway regulator CSF-1R is thought to play an essential role in the recruitment and differentiation of macrophages. The CSF-1R kinase inhibitors have entered clinical trials for various cancer treatments (133). Stephanie et al used the CSF-1R inhibitor BLZ945 to target GAMs in a mouse proneural GBM model, which revealed an improved survival and regression of established tumors in treated mice.…”

Section: Research Progresses In Targeting Gams For the Treatment Of G...mentioning

confidence: 99%

Section: Research Progresses In Targeting Gams For the Treatment Of Gbmmentioning

confidence: 99%

Origin, activation, and targeted therapy of glioma-associated macrophages

Cheng

Xiao²,

Li³

et al. 2022

Front. Immunol.

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The glioma tumor microenvironment plays a crucial role in the development, occurrence, and treatment of gliomas. Glioma-associated macrophages (GAMs) are the most widely infiltrated immune cells in the tumor microenvironment (TME) and one of the major cell populations that exert immune functions. GAMs typically originate from two cell types-brain-resident microglia (BRM) and bone marrow-derived monocytes (BMDM), depending on a variety of cytokines for recruitment and activation. GAMs mainly contain two functionally and morphologically distinct activation types- classically activated M1 macrophages (antitumor/immunostimulatory) and alternatively activated M2 macrophages (protumor/immunosuppressive). GAMs have been shown to affect multiple biological functions of gliomas, including promoting tumor growth and invasion, angiogenesis, energy metabolism, and treatment resistance. Both M1 and M2 macrophages are highly plastic and can polarize or interconvert under various malignant conditions. As the relationship between GAMs and gliomas has become more apparent, GAMs have long been one of the promising targets for glioma therapy, and many studies have demonstrated the therapeutic potential of this target. Here, we review the origin and activation of GAMs in gliomas, how they regulate tumor development and response to therapies, and current glioma therapeutic strategies targeting GAMs.

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Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors

Cited by 17 publications

References 18 publications

Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues

Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues

Candidate Tracers for Imaging Colony-Stimulating Factor 1 Receptor in Neuroinflammation with Positron Emission Tomography: Issues and Progress

Origin, activation, and targeted therapy of glioma-associated macrophages

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