Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor

Tap, William D.; Wainberg, Zev A.; Anthony, Stephen P.; Ibrahim, Prabha; Zhang, Chao; Healey, John H.; Chmielowski, Bartosz; Staddon, Arthur P.; Cohn, Allen Lee; Shapiro, Geoffrey I.; Keedy, Vicki L.; Singh, Arun S.; Puzanov, Igor; Kwak, Eunice L.; Wagner, Andrew J.; Hoff, Daniel D. Von; Weiss, Glen J.; Ramanathan, Ramesh K.; Zhang, Jiazhong; Habets, Gaston; Zhang, Ying; Burton, Elizabeth A.; Visor, Gary C.; Sanftner, Laura; Severson, Paul; Nguyen, Hoa; Kim, Marie J; Marimuthu, A.; Tsang, Garson; Shellooe, Rafe; Gee, C. N. P.; West, Brian L.; Hirth, Peter; Nolop, K. B.; Rijn, Matt van de; Hsu, Henry H.; Peterfy, Charles; Lin, Paul S.; Tong-Starksen, Sandra; Bollag, Gideon

doi:10.1056/nejmoa1411366

Cited by 454 publications

(487 citation statements)

References 20 publications

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“…PLX5622 is a more specific (i.e., the compound does not inhibit c‐Kit) sister molecule of the clinically utilized CSF1R inhibitor PLX3397 (Butowski et al, 2016; Tap et al, 2015). This treatment eliminated ~85% of microglia throughout the CNS (Supporting Information Figure S1a–c).…”

Section: Resultsmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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Section: Resultsmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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“…All tumors from these patients had high levels of CSF1 expression. However, it remains undetermined whether the presence of specific translocation between chromosomes 1 and 2, which is found in some but not all patients with this tumor, correlates with the positive response [13,15] . X-ray crystallographic studies of PLX3397 revealed sites of potential interest in promoting strong drug-protein interaction.…”

Section: New Generation Of Molecules Inhibiting Csf1rmentioning

confidence: 97%

“…Its selectivity may be attributed to its unique interaction with the JM domain. Selectivity and increased potency for CSF1R may be an important factor in its superior clinical activity in patients with CSF1-dependent TGCTs [13,15] . The design of PLX3397 represented an advancement of current drug-development research.…”

Section: New Generation Of Molecules Inhibiting Csf1rmentioning

confidence: 99%

“…Besides, X-ray crystallography can also predict which modifications of an inhibitor will enhance the potency for a specific protein conformation. Despite its potency, PLX3397 causes a spectrum of toxic effects (e.g., liver-enzyme elevations and severe fatigue) that necessitated dose reductions or drug holidays in one-third of patients [13,15] . Clearly, CSF1R inhibition using selective CSF1R inhibitors warrants further study in prospective randomized clinical trials and could potentially assist the improved management of such disease.…”

Section: New Generation Of Molecules Inhibiting Csf1rmentioning

confidence: 99%

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Tenosynovial Giant Cell Tumor: Better molecular understanding revolutionizes treatment outcome

Shash

2016

Adv Mod Oncol Res

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Tenosynovial giant cell tumors (TGCTs) are rare tumors, which are primarily treated via surgery with a low likelihood of metastasis. Although wide excision is an excellent choice for local control, tumors located within or close to major joints, along with the benign nature of the disease, make such resection impractical. An increase in local recurrences and the need for multiple surgical procedures promoted the interest in targeted-therapies for this disease. TGCTs contain a mixture of giant cells, mononuclear cells and inflammatory cells, with clonal cytogenetic abnormalities through rearrangements involving 1p11-13. Colony stimulating factor (CSF1) gene encodes for the ligand of CSF1 receptor (CSF1R). The CSF1 gene is located at the chromosome 1p13 breakpoint and is found to be translocated in 63%-77% of patients with TGCTs. Selective CSF1R inhibitors yield high response rate and disease control, demo nstrating the integration of a new drug development technology that could revolutionize treatment outcomes.

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“…10) Figure 1b shows representative kinase inhibitors having a number of substituents at various positions in the 7-azaindole ring. [11][12][13][14][15][16] Among them, vemurafenib (1), a B-RAF kinase (serinethreonine kinase [STK]) inhibitor, is the first FDA-approved 7-azaindole-based kinase drug for the treatment of melanoma.…”

Section: Introductionmentioning

confidence: 99%

7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors

Irie¹,

Sawa²

2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor

Abstract: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).

Cited by 454 publications

References 20 publications

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Tenosynovial Giant Cell Tumor: Better molecular understanding revolutionizes treatment outcome

7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors

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