Targeting these macrophages with the GW2580 CSF1R inhibitor leads to restored immune surveillance and improved survival. Overall, we demonstrate that circulating macrophages are responsible, at least in part, for the immune suppression in SCLL leukemia models, and targeting macrophages in this system improves the survival of leukemic mice.

Further, six drugs (Vinorelbine, GW-2580, S-Trityl-L-cysteine, BI-2536, CP466722, NSC-87877) were found to be correlated with the RiskScore. In addition, KRT19 silencing markedly inhibited the invasion and migration of OC cells. This study established a relapse-related RiskScore model based on five prognostic genes (LDHA, NOP58, NMU, KRT19, and RPS23), offering novel insights into the recurrence mechanisms in OC and contributing to the development of individualized treatment strategies.

Furthermore, G-749 is screened and identified as a novel NAT10 inhibitor capable of effectively impeding lysosomal acidification and tumor metastasis by disrupting the NAT10-Ubiquitin-specific Peptidase 39 (USP39) interaction. Overall, the results unveil a novel role of ac4C modifications in regulating lysosomal acidification and propose a potential strategy by targeting NAT10 to inhibit esophageal cancer metastasis.

The ZMYM2-ANXA9 signaling axis drives chemoresistance and tumor progression in CRC. FLT3 inhibition by G749 effectively downregulates ANXA9 and sensitizes tumors to chemotherapy, highlighting a novel therapeutic approach for chemoresistant CRC.

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.

In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.

To discover next-generation FLT3 inhibitors and gather additional structure-activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies...Furthermore, it significantly reduced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP), and strongly inhibited FLT3-mediated signaling pathways. These findings, along with the obtained SAR information, provide valuable insights for the further development of FLT3 inhibitors.

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.

To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk-RNA sequencing data from 21 NSCLC patients undergoing anti-PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti-PD-1 immunotherapy, suggesting a role for NLRP3 inflammasome in activating immune responses during treatment.

P1, N=36, Active, not recruiting, Oscotec Inc. | Recruiting --> Active, not recruiting

P1, N=14, Completed, Oscotec Inc. | Unknown status --> Completed | N=40 --> 14