mivavotinib (CB-659)

Despite the investigation of inhibitors of SYK including fostamatinib, entospletinib, cerdulatinib, and TAK-659 for cancer therapy, their lack of specificity and potential off-target effects remain significant concerns...Rifabutin, darunavir, and sildenafil were found as promising SYK inhibitors, showing strong interactions and stable conformations...Our findings underscore the value of computational methods in drug discovery and advocate for further experimental validation of these compounds as SYK-targeted therapies. This study aims to advance the development of more effective and safer treatments for cancers associated with SYK overexpression.

P1, N=12, Completed, Northwestern University | Active, not recruiting --> Completed

This study investigates in vitro antiproliferative effects of SYK inhibitors on leukemia cells by analyzing 48 primary AML samples treated with five SYK inhibitors: fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021. Gene set enrichment analysis further highlighted that high-sensitivity patient samples were upregulated in pathways associated with oxidative phosphorylation and MYC targets, whereas low-sensitivity patient samples showed enrichment in TGF beta signaling and IL6 JAK STAT3 signaling. These results identify gene expression profile signatures that may predict sensitivity to SYK inhibition and underscore the potential for personalized therapeutic strategies in AML.

P1, N=12, Active, not recruiting, Northwestern University | Completed --> Active, not recruiting | Trial completion date: Dec 2024 --> Dec 2028

P1, N=12, Completed, Northwestern University | Active, not recruiting --> Completed | Trial completion date: Aug 2022 --> Dec 2024

The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.

We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023...The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.

Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.

A TAK-659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R-CHOP and TAK-659 in patients with newly diagnosed high-risk DLBCL produces promising CR rates.

These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934.