sotuletinib (BLZ-945)

Upon doxycycline withdrawal at 8 weeks of age, mice developed progressive cerebellar ataxia by 26 weeks and succumbed by 30 weeks...Prophylactic administration of the CSF1R inhibitor BLZ945 exacerbated motor deficits and demyelination, significantly increasing this microglial population. Similarly, MSR1+ and CD68+ microglia/macrophages were observed in early pontocerebellar lesions of six human MSA-C autopsy cases. These findings suggest that this pro-inflammatory microglia subset plays a central role in disease progression and may represent a promising therapeutic target for modifying the course of MSA-C and related synucleinopathies.

Functional validation was conducted using a ccRCC xenograft mouse model treated with the CSF1R inhibitor Sotuletinib...Importantly, CellChat-based predictions represent potential, rather than definitive, ligand-receptor interactions, and thus require further mechanistic validation. Targeting CSF1R may offer a promising strategy to modulate the immune landscape and improve therapeutic outcomes in ccRCC.

This system, MRC1-targeting peptide-M@BLZ945 (PMMB), integrates a colony-stimulating factor 1 receptor (CSF-1R) inhibitor and a STING agonist within a macrophage-mimetic nanostructure, enabling sequential, controlled reprogramming of TAMs...These findings establish spatiotemporal macrophage circuit engineering via STING phase separation as a cross-scale strategy to override PDAC's immune barriers and drive next-generation macrophage-targeted immunotherapy. This study paves the way for rationally designed, precision macrophage modulation strategies in solid tumors.

Furthermore, BMS777607, a receptor tyrosine kinase inhibitor capable of repolarizing M2 macrophages in vitro, reduced organoid viability via a macrophage-dependent mechanism...A TAM-targeted CSF-1 R inhibitor, BLZ945, combined with paclitaxel reduced tumor burden with no regrowth, suggesting that TAMs promote paclitaxel resistance in this model. Our study demonstrates that TAMs influence response to paclitaxel in both patient-derived OC organoids and huPDX. These models are useful for evaluating immunomodulatory therapy effects and could serve as a robust platform for preclinical testing of novel anti-cancer treatments, providing insights into the complex interplay between immune cells and cancer therapeutics.

These results suggest that [11C]FJRD is a potential CSF1R-PET tracer for more sensitive detection of CSF1R, compared to [11C]CPPC and [11C]GW2580. However, the high level off-target binding necessitates further improvements in specificity for CSF1R imaging.

Addition of cold CPPC partially blocked in - vitro [ 11 C]FJRD binding in the various organs with blocking effects from 9 to 67%, and other two CSF1R inhibitors, GW2580 and BLZ945, showed minimal blocking effect, suggesting unignorable off-target binding in these organs. Conclusions These results suggest [ 11 C]FJRD as a potential CSF1R-PET tracer for more sensitively detecting CSF1R compared to [ 11 C]CPPC and [ 11 C]GW2580. However, high-level off-target binding requires further improvement in specificity for CSF1R imaging.

Targeting TAMs via CSF1R inhibition enhances the therapeutic efficacy of cisplatin in HNSCC. These findings suggest that CSF1R inhibitors hold promise as a component of combination therapy for HNSCC.

More importantly, we found that Proguanil's inhibitory effect on U87MG cell growth and migration was positively correlated with CSF1R expression, and this effect diminished following CSF1R knockdown and Proguanil demonstrated synergistic effects with CSF1R-targeting positive drugs (BLZ945 and GW2580). Meanwhile, Proguanil targeted CSF1R to inhibit M2-type polarization of tumor-associated macrophages (TAMs) and their proliferation, thus altering the tumor microenvironment while indirectly suppressing the proliferation and migration of U87MG cells. Taken together, these findings suggest that Proguanil may serve as a promising CSF1R antagonist for GBM treatment.

P2, N=28, Terminated, Novartis Pharmaceuticals | N=56 --> 28 | Trial completion date: Jun 2026 --> Feb 2024 | Recruiting --> Terminated | Trial primary completion date: Mar 2025 --> Feb 2024; Study terminated after assessment of potential benefit-risk from available data

P2, N=56, Recruiting, Novartis Pharmaceuticals | Active, not recruiting --> Recruiting

P2, N=56, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human glioblastoma avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for glioblastoma.