denfivontinib (SKI-G-801)

Guided by a scaffold-hopping strategy based on G-749 (denfivontinib), a series of quinazoline-based derivatives was designed and synthesized to explore structure-activity relationships (SAR)...Mechanism studies indicated that W4 induced G0/G1 cell cycle arrest and apoptosis, accompanied by a reduction in intracellular reactive oxygen species levels and a loss of mitochondrial membrane potential. Collectively, these results identified W4 as a potent FLT3 inhibitor and provided valuable SAR insights for further scaffold optimization.

P1, N=28, Recruiting, Grit Biotechnology

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.

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.

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

In this study, we examined the effect of AXL inhibitors on immune activation and tumor growth in TC1 and C3PQ mouse tumor models, in the context of clinical immunotherapy/chemotherapy and maintenance treatment, using an aPD-1 with/without pemetrexed. These results suggest increased infiltration of T cells, consistent with previous studies using AXL inhibitors. It is expected that the results from this study will serve as a stepping stone for clinical research to improve the existing standard of care.

SKI-G-801 significantly suppressed tumor metastasis and growth by enhancing anti-tumor immune responses. Our results suggest that SKI-G-801 has the potential to overcome anti-PD-1 therapy resistance and allow more patients to benefit from anti-PD-1 therapy.

G-749, a potential TAM receptor tyrosine kinase inhibitor, and its derivative SKI-G-801, effectively inhibits the phosphorylation of AXL at nanomolar concentration (IC = 20 nM)...In addition, we demonstrated that G-749 inhibits the signaling pathway associated with cell proliferation in colon cancer cell lines HCT15 and SW620, as well as tumor xenograft mouse models. We propose G-749 as a new therapeutic agent for the treatment of colon cancer caused by abnormal TYRO3 expression or activity.