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

We show that MLS cooperates with KA1 to regulate MELK localization and is necessary to induce cytokinesis failure when MELK is overexpressed. Our findings highlight the importance of MLS in MELK localization and in regulating MELK activity.

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.

This exploration not only promises to enhance our understanding of cancer's molecular underpinnings but also opens up avenues for developing novel targeted interventions. The rationale behind focusing on MELK-ncRNA crosstalk lies in the potential to disrupt these critical molecular interactions, thereby offering a novel strategy to counteract cancer progression and improve treatment outcomes.

KA1 domains are known to regulate kinase activities through various intramolecular interactions. Our results revealed a new role for KA1 domain to control subcellular localization of a protein kinase.

A comprehensive understanding of MELK may provide clues and confidence for subsequent basic research and scientific transformation. In this review, we provide a comprehensive overview of the structural features, molecular biological functions, and critical roles of MELK in tumors and TME, as well as the targeted agents under development for the treatment of tumors and discuss the perspective for MELK-targeted therapies for tumors.

Our investigation underscores the critical role of MELK in promoting chemoresistance and inducing M2 macrophage polarization in GC. It proposes novel targets and methods for the treatment of GC, as well as prognostic factors for neoadjuvant chemotherapy.