OTS167

The YAP inhibitor Verteporfin blunted MELK-driven PASMC proliferation and migration, underscoring the central role of YAP/TAZ signaling. Finally, in vivo pharmacological inhibition of MELK by OTS167 markedly reduced right ventricular systolic pressure, hypertrophy, and pulmonary vascular remodeling in Su/H mice, confirming the therapeutic relevance of MELK targeting in PAH. Collectively, these findings identify MELK as a novel regulator of PASMC pathobiology in PAH and suggest that it may represent a potential therapeutic target.

P1, N=70, Recruiting, OncoTherapy Science, Inc. | Active, not recruiting --> Recruiting

ROS scavenging via N-acetylcysteine (NAC) reverses these effects, confirming ROS as the central mediator of antitumor activity of OTSSP167. These findings unveil a redox-centric mechanism by which OTSSP167 disrupts TNBC progression, positioning it as a promising therapeutic candidate for combating TNBC BM. The study underscores the translational relevance of targeting MELK and ROS-dependent kinase networks to address unmet clinical needs in TNBC management.

Finally, we demonstrated that combining OTS167 with zanamivir or oseltamivir resulted in additive antiviral activity. In conclusion, we identified MELK as a crucial host kinase that supports the influenza virus infection. OTS167, a pharmacological inhibitor of MELK currently undergoing phase II clinical trials for treating cancer, potently inhibits influenza virus infections in vitro and in mice, representing a promising lead for developing novel influenza antivirals.

P1, N=70, Active, not recruiting, OncoTherapy Science, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Aug 2024 --> Sep 2027 | Trial primary completion date: Aug 2024 --> Sep 2027

Furthermore, in nude mice with transplanted tumor, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment.

Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

Finally, MELK overexpression conferred tolerance to PD-1 blockade in cervical tumors, whereas targeting MELK by OTSSP167 significantly enhanced PD-1 blockade efficiency. Our data elucidated a novel role of MELK in regulating Th1/Th2 balance and anti-PD-1 immunotherapy in cervical cancer.

We found that MELK acts downstream of Del-1 and is a promising druggable target, especially in basal-like and mesenchymal stem-like subtype.

We confirmed that NLK activity was increased in erythroid progenitors from the Rpl11-haploinsufficient mice for in vitro phosphorylation of the substrate compared with tamoxifen-treated wild type mice...We have initiated studies to test the efficacy of OTS167 in vivo using Rpl11-haploinsufficient mouse models. Given that DBA is associated with a number of mutations in the ribosome, using one drug that targets NLK as a common therapeutic target could be a more practical treatment option for patients in contrast to gene therapy or gene editing followed by autologous stem cell rescue. Even if the drug targeting NLK does not completely rescue the anemia in ribosome-insufficient cell models of DBA, the improvement could be enough to help patients especially in combination with other drugs that are currently being used or studied.

CIT kinase activity was identified as druggable and was potently inhibited by the multi-kinase inhibitor OTS-167, which decreased proliferation of treatment-resistant PCa cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant PCa. These findings provide insights into regulation of aggressive PCa cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of PCa progression.

Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting Δ40p53 in tumours that have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin.