SIK3

Researchers found that, in neurons that produced the neuropeptide NMS, the interaction between molecules SIK3 and HDAC4 has a critical role in sleep regulation through both the length of the circadian period and sleep homoeostasis. Given the similarities among different mammals, new information about how the circadian system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans. Most living creatures exhibit a circadian rhythm, an internal clock that repeats around every 24 hours. Now, researchers from Japan have found new details about the molecular processes that govern sleep/wake rhythms in mice. In a recently published study, researchers from the University of Tsukuba have revealed that a key molecule involved in sleep homeostasis (called SIK3 or salt-inducible kinase 3) also plays a critical role in circadian behavior. Animals are able to adapt to the 24-hour cycle of light and dark in terms of both behavior and physiology via changes in the suprachiasmatic nucleus (SCN), which is the brain's master clock that synchronizes the various rhythms in the body. However, the biological activities within the SCN that induce time-specific wakefulness have not been fully characterized; the research team aimed to address this. "Most animals show a peak in activity at a specific point in the circadian cycle," explains lead author of the study Professor Masashi Yanagisawa. "Because the SCN has been found to regulate sleep and wakefulness at certain times of the day, we wanted to investigate the distinct neurons that control this process." To do this, the research team genetically manipulated levels of SIK3 in specific neuron groups in the SCN of mice. Then, they examined sleep and circadian behaviors in the mice, such as when and for how long the mice exhibited activity with respect to the light-dark cycle. "We found that SIK3 in the SCN can influence circadian cycle length and the timing of peak arousal activity, without changing the daily sleep amount," says Professor Yanagisawa. The research team previously reported that SIK3 interacts with LKB1 (an upstream molecule of SIK3) and HDAC4 (an important target of SIK3) in glutamatergic neurons to regulate the amount and depth of sleep. Now, they have found that the SIK3-HDAC4 pathway modulates the length of the circadian period through NMS-producing neurons, and contributes to the sleep/wake rhythm. The length of the behavioral period and the timing of peak activity are important components of the circadian rhythm. Given the similarities between the circadian systems of different mammals, new information about how this system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans. This work was supported by the World Premier International Research Center Initiative (WPI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI), Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), JSPS DC2 grant, University of Tsukuba Basic Research Support Program Type A, and Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).

First-in-human trial to test safety and tolerability of a novel immune-protective kinase inhibitor in multiple solid tumors. First iOTarg platform-derived product candidate in the clinic. Martinsried / Munich, Germany, 04 April 2023 - iOmx Therapeutics AG, a biopharmaceutical company developing next-generation targeted cancer immunotherapy treatments, today announced the dosing of the first patient in a Phase I dose escalation study evaluating OMX-0407, a first-in-class oral SIK (salt-inducible kinase) inhibitor. The study is a single-arm, open-label, multicenter, Phase I clinical trial assessing the safety and tolerability of OMX-0407 as monotherapy in patients with previously treated unresectable solid tumors. The clinical trial has been approved by regulators in Spain and Belgium. “With an exciting novel mode of action OMX-0407 holds the potential to address multiple solid tumors that are not responsive to conventional immune checkpoint inhibitors. Our research has shown that inhibition of SIK with OMX-0407 potentiates tumor cell apoptosis by un-leashing intra-tumoral death receptor signaling resulting in anti-tumor efficacy in pre-clinical models resistant to conventional immune checkpoint blockade,” said Dr. Murray Yule, Chief Medical Officer of iOmx. “We would like to express our gratitude to the investigators, their teams and the patient community for their support and trust in our treatment approach with OMX-0407.” Dr. Apollon Papadimitriou, CEO of iOmx added: “We are proud to bring our first iOTarg platform-derived product candidate into the clinic. This is a significant milestone for iOmx as we pursue our goal to deliver better medical options for patients failing current cancer immunotherapy treatments.” SIK family member SIK3 was identified as a novel immune-protective kinase by using iOmx’s systematic screening platform, iOTargTM. Inhibition of SIK3 with OMX-0407 targets a novel immune evasion biology by sensitizing tumors to immune-derived ligands of the TNF superfamily. In preclinical studies OMX-0407 showed strong monotherapy effects reshaping the immune compartment and accelerating tumor cell death. About OMX-0407 OMX-0407 is an oral spectrum-selective salt-inducible kinase (SIK) inhibitor. The SIK family member SIK3 is known for regulating the NF-κB driven gene landscape through phosphorylation of class IIa histone deacetylases (HDACs) and CREB-regulated transcriptional coactivators causing the tumor to evade death receptor-mediated killing. Downregulation of this pathway with OMX-0407 potentiates apoptosis by death receptor ligands, such as tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL) in preclinical studies. About the study The study is a first-in-human, dose-escalation trial of OMX-0407 monotherapy in patients with previously treated unresectable solid tumors. The Phase I trial is designed to characterize the safety, tolerability and pharmacodynamic activity of OMX-0407. The dose escalation scheme is established on the 3+3 design to determine the maximum tolerated dose (MTD). About iOmx Therapeutics iOmx Therapeutics ( ) is a biopharmaceutical company focused on developing first-in-class cancer immuno-therapeutics addressing novel immune checkpoints hijacked by cancer cells. Utilizing its iOTarg™ high-throughput screening platform, iOmx has identified a number of proprietary tumor-associated next-generation immune checkpoints and is advancing a preclinical stage pipeline of promising drug candidates that have the potential to address cancers that are resistant to current immunotherapies. The company’s lead compound OMX-0407 targets SIK, an immune protective kinase family in multiple solid tumors. Founded in 2016 based on the work of its scientific founders Philipp Beckhove, MD, and Nisit Khandelwal, Ph.D., conducted at the German Cancer Research Center, iOmx is backed by international venture capital investors, such as Wellington Partners, Sofinnova Partners and M Ventures as well as MIG Capital and Athos Biopharma. iOmx is based in Martinsried/Munich, Germany. Media contact MC Services AG Katja Arnold, Julia von Hummel, Shaun Brown T: +49(0)89 2102280 iomx@mc-services.eu

Discovery of novel immune checkpoints in the tumor microenvironment with iOTarg™ screening platformPredictive biomarker signature for lead product candidate OMX-0407 MUNICH, Germany, March 15, 2023 (GLOBE NEWSWIRE) -- iOmx Therapeutics AG, a biopharmaceutical company developing cancer therapeutics based on next generation immune checkpoint targets, today announced that its high-throughput target discovery platform, myeloid iOTargTM, will be highlighted in an oral presentation at the American Association for Cancer Research (AACR) Annual Meeting 2023. Further, the company will present new data on its lead product candidate, OMX-0407, in a poster presentation at the conference, which will take place from April 14 to 19 in Orlando, Florida. “We are excited to present our latest achievements in discovering and addressing novel immune evasion biology at this year’s AACR Annual Meeting,” said Dr. Nisit Khandelwal, Founder and Head of Research at iOmx. “In addition to tumor cells themselves, the tumor microenvironment, especially tumor-associated macrophages, play an important role in the immune escape mechanisms of solid tumors. We have leveraged our powerful discovery engine, iOTarg, to understand and uncover the entire repertoire of immune-modulating targets expressed on myeloid cells in an unbiased high-throughput manner. Identification of novel immune checkpoints on myeloid cells will enable us to further unlock the immune system’s ability to fight cancer and to address tumors that are resistant to current immunotherapies.” “Our first iOTarg platform derived product candidate, OMX-0407, an orally available SIK (salt-inducible-kinase) inhibitor, will soon be tested in the clinic. We will present new data on the predictive biomarker signature for this candidate, which will be evaluated during our clinical development strategy,” said Dr. Christine Rothe, Chief Development Officer at iOmx. Oral Presentation: A function-based high-throughput discovery platform, myeloid iOTargTM, identifies novel immune checkpoints of the tumor microenvironment.Abstract Number: 3471Session and Date: Immune Checkpoints at Tumor Beds, April 17, 2023, 2:30 PM ET In this oral presentation the company will present its systematic screening approach for key mediators of tumor-associated macrophages (TAMs) induced immunosuppression. Using CRISPR-edited macrophages in a co-culture system, the myeloid iOTargTM platform allows to systematically address the functional role of any TAM-expressed gene in the regulation of macrophage phenotype, T cell activity, and gross impact on tumor cell lysis in a high-throughput, mixed cell type culture setting. The assay read-outs confirmed well-known targets, and identified additional novel targets that could lead to novel first-in-class tumor microenvironment-based therapeutics. Poster Presentation: Development of a predictive biomarker signature for the highly potent SIK3 inhibitor OMX-0407Abstract Number: 953/4Session and Date: Biomarkers of Therapeutic Benefit 1, April 16, 2023, 1:30 PM ET The poster describes the identification and validation of a response-prediction biomarker signature for its orally available first-in-class SIK (salt-inducible kinase) inhibitor lead product candidate OMX-0407. Using comprehensive transcriptomics and proteomics analyses the selective activity profile of OMX-0407 on individual cancer cell lines and PDX models was used to identify and validate a predictive biomarker signature. With this gene signature, 84% of the selected cancer cells lines were correctly classified and would benefit from OMX-0407 therapy. The predictive biomarker will be evaluated in the clinical phase I trial of OMX-0407 scheduled to start enrollment shortly. About iOmx Therapeutics iOmx Therapeutics (www.iomx.com) is a biopharmaceutical company focused on developing first-in-class cancer immuno-therapeutics addressing novel immune checkpoints hijacked by cancer cells. Utilizing its iOTarg™ high-throughput screening platform, iOmx has identified a number of proprietary tumor-associated next-generation immune checkpoints and is advancing a preclinical stage pipeline of promising drug candidates that have the potential to address cancers that are resistant to current immunotherapies. The company’s lead program IMT-07 targets SIK3, an immune protective kinase in multiple solid tumors. Founded in 2016 based on the work of its scientific founders Philipp Beckhove, MD, and Nisit Khandelwal, Ph.D., conducted at the German Cancer Research Center, iOmx is backed by international venture capital investors, such as Wellington Partners, Sofinnova Partners and M Ventures as well as MIG Capital and Athos Biopharma. iOmx is based in Martinsried/Munich, Germany. Contact MC Services AGKatja Arnold, Julia von Hummel, Shaun BrownT: +49(0)89 2102280iomx@mc-services.eu