tirbanibulin oral (KX2-391 oral)

Tirbanibulin 1% ointment is a synthetic antiproliferative agent approved in 2021 by the European Union for treating actinic keratoses (AK). These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins via the Src- MEK- pathway. Tirbanibulin significantly downregulates oncogenic proteins related to cell cycle regulation and cell proliferation while upregulating apoptosis pathways.

In a murine wound infection with vancomycin-resistant Enterococcus faecalis, a single intraperitoneal bosutinib injection or multiple topical applications on the wound reduce the bacterial load by approximately 10-fold, which is abolished by macrophage depletion...Other Src kinase inhibitors such as DMAT and tirbanibulin also upregulate expression of bacterial uptake markers in macrophages and enhance intracellular bacterial killing. Finally, cotreatment with bosutinib and mitoxantrone, another chemotherapeutic in clinical use, results in an additive effect on bacterial clearance in vitro and in vivo. These results show that bosutinib stimulates macrophage clearance of bacterial infections through multiple mechanisms and could be used to boost the host innate immunity to combat drug-resistant bacterial infections.

While it showed confirmed inhibitory activity against cancer cells, this substitution shifted the profile of affected targets away from Src/tubulin which were seen with the parent KX-01...Both compounds exhibited profound downregulation effects on Erk1/2 but differed on others such as GSK3α/β and C-Jun. Collectively, this study further support to the hypothesis that small structural changes might bring higher changes in their kinome profile.

OBJECTIVES: To investigate if LC-OCT may be useful in monitoring AKs changes during treatment with tirbanibulin 1% ointment. Although some limitations of our pilot study include the small sample size and the lack of biopsy before and after treatment, it confirms the efficacy and safety of tirbanibulin in treating AKs and the usefulness of LC-OCT for the therapeutic monitoring of skin tumors along with the identification of signs of apoptosis and inflammation resulting from such treatments

There are reports of successful use of topical imiquimod, photodynamic therapy (PDT) and topical 5-fluorouracil with recurrence when treatment is discontinued...He previously applied topical imiquimod, discontinued due to systemic reaction, ingenol mebutate, 5-fluorouracil, and performed PDT with low benefits...For these reasons, we used tirbanibulin ointment on the area of previous surgery and on the peripheral area (right hemi- frontal), applying it once a day for 2 cycles of 5 days with 14 days of break between the 2 cycles...Tirbanibulin has a selective action against cells that most express microtubules and its action is, ideally, to be considered more effective the greater the number of mitoses. Based on this reasoning, we used tirbanibulin in the treatment of iSCC, not as an alternative to the surgical proposal, which always remains the first-line of therapy, but as an adjuvant approach in a selected patient to reduce the risk of progression, waiting for a possible wide local excision.

Although the etiology remains unknown, its development has been associated with several factors, the most important of which is represented by trauma, sunburns, medical procedures, and topical medications, including those used to treat actinic keratoses such as imiquimod and fluorouracil. Results Tirbanibulin showed low impact on EPDS, causing only a mild worsening of the symptoms easily controlled with a short course of topical steroids while maintaining high efficacy with regard to actinic keratoses and the field of cancerization. Discussion From our experience, topical tirbanibulin is a treatment to be considered in this type of patients, as tirbanibulin induces apoptosis and not necrosis resulting in less release of proinflammatory cytokines and reduced inflammatory stimulation in comparison with other treatments in use for actinic keratoses.

These results suggested that PDGF-Rβ and SRC can be used as drug targets for suppressing NPC metastasis. Indeed, our in vivo assay using the SRC inhibitor KX2-391, clearly showed that inhibition of SRC signaling can prevent the metastasis of NPC, indicating that targeting SRC can be a promising approach to control the NPC progression.

Furthermore, the combination of the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 dramatically suppressed ELF4-mediated CRC metastasis. We demonstrated the essentiality of ELF4 in the metastatic process of CRC, and targeting the ELF4-relevant positive feedback circuit might represent a novel therapeutic strategy.

Additionally, high-risk patients generally exhibited higher response to chemotherapeutic agents (cisplatin, etc.). We also predicted several small molecule compounds (GSK461364, KX2-391, etc.) for treating this subset. Accordingly, this cuproptosis-relevant lncRNA signature offers an efficient approach to identify and characterize diverse prognosis, genomic alterations, and treatment outcomes in LUAD, thus potentially assisting personalized therapy.

Kinase profiling using two methods revealed that 4e significantly reduces the activities of some other potent oncogenic kinases like the MAPK member ERK1/2 (>99%) and it also greatly upregulates the pro-apoptotic c-Jun kinase (84%). This research also underscores the importance of thorough investigation of total kinase activities as part of the structure-activity relationship studies.

Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor.

We sought to study tirbanibulin, a first-in-class dual Src kinase (non-ATP competitive)/tubulin inhibitor because there was not enough reporting about its structure-activity relationships (SARs)...It also strongly suppresses signals of ERK1/2, GSK-3α/β, HSP27, and STAT2, while it downregulated AMPKα1 phosphorylation within the HL60 cells. Collectively, these results suggest that phenylacetamide-1H-imidazol-5-one (KIM-161) could be a promising lead compound for further clinical anticancer drug development.

KX2-391 exhibited potent growth inhibitory and apoptosis promoting effects on diverse AML cell lines harboring FLT3-ITD mutations and AC220-resistant mutations at the D835 and F691 residues in TKD and inhibited FLT3 phosphorylation and its downstream signaling targets. KX2-391 also significantly inhibited the growth of 4 primary AML cells expressing FLT3-ITD and 2 primary AML cells expressing FLT3-ITD-D835Y. Our preclinical data highlight KX2-391 as a promising FLT3 inhibitor for the treatment of AML patients harboring FLT3 mutations, especially refractory/relapsed patients with F691L and other FLT3-TKD mutations.

Down-regulation of SRC (p<0.01) or SIRT1 (p<0.05) separately reversed the resistance to tamoxifen and the minimal concentration of SRC inhibitor KX-01 (p<0.05) or SIRT1 inhibitor EX527 (p<0.001) could also suppress cell proliferation. Moreover, SRC could promote tamoxifen resistance by up-regulating SIRT1. SRC and SIRT1 might be novel therapeutic targets in tamoxifen-resistant breast cancer and the interaction between SRC and SIRT1 needs to be further explored.